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Supplemental Digital Content is available in the text., Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

BACKGROUND: Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome; SADS) may identify relatives at risk of fatal arrhythmias.OBJECTIVES: This study aimed to assess the impact of systematic ajmaline provocation testing using high right precordial leads (RPLs) on the diagnostic yield of Brugada syndrome (BrS) in a large cohort of SADS families.METHODS: Three hundred three SADS families (911 relatives) underwent evaluation with resting electrocardiogram using conventional and high RPLs, echocardiography, exercise, and 24-h electrocardiogram monitor. An ajmaline test with conventional and high RPLs was undertaken in 670 (74%) relatives without a familial diagnosis after initial evaluation. Further investigations were guided by clinical suspicion.RESULTS: An inherited cardiac disease was diagnosed in 128 (42%) families and 201 (22%) relatives. BrS was the most prevalent diagnosis (n = 85, 28% of families; n = 140, 15% of relatives). Ajmaline testing was required to unmask the BrS in 97% of diagnosed individuals. The use of high RPLs showed a 16% incremental diagnostic yield of ajmaline testing by diagnosing BrS in an additional 49 families. There were no differences of the characteristics between individuals and families with a diagnostic pattern in the conventional and the high RPLs. On follow-up, a spontaneous type 1 Brugada pattern and/or clinically significant arrhythmic events developed in 17% (n = 25) of the concealed BrS cohort.CONCLUSIONS: Systematic use of ajmaline testing with high RPLs increases substantially the yield of BrS in SADS families. Assessment should be performed in expert centers where patients are counseled appropriately for the potential implications of provocation testing.

OBJECTIVES: The authors studied the response rates and relative sensitivity of the most common agents used in the sodium-channel blocker (SCB) challenge. BACKGROUND: A type 1 Brugada electrocardiographic pattern precipitated by an SCB challenge confers a diagnosis of Brugada syndrome. METHODS: Patients undergoing an SCB challenge were prospectively enrolled across Canada and the United Kingdom. Patients with no prior cardiac arrest and family histories of sudden cardiac death or Brugada syndrome were included. RESULTS: Four hundred twenty-five subjects underwent SCB challenge (ajmaline, n = 331 [78%]; procainamide, n = 94 [22%]), with a mean age of 39 ± 15 years (54% men). Baseline non-type 1 Brugada ST-segment elevation was present in 10%. A total of 154 patients (36%) underwent signal-averaged electrocardiography, with 41% having late potentials. Positive results were seen more often with ajmaline than procainamide infusion (26% vs. 4%, p < 0.001). On multivariate analysis, baseline non-type 1 Brugada ST-segment elevation (odds ratio [OR]: 6.92; 95% confidence interval [CI]: 3.15 to 15.2; p < 0.001) and ajmaline use (OR: 8.76; 95% CI: 2.62 to 29.2; p < 0.001) were independent predictors of positive results to SCB challenge. In the subgroup undergoing signal-averaged electrocardiography, non-type 1 Brugada ST-segment elevation (OR: 9.28; 95% CI: 2.22 to 38.8; p = 0.002), late potentials on signal-averaged electrocardiography (OR: 4.32; 95% CI: 1.50 to 12.5; p = 0.007), and ajmaline use (OR: 12.0; 95% CI: 2.45 to 59.1; p = 0.002) were strong predictors of SCB outcome. CONCLUSIONS: The outcome of SCB challenge was significantly affected by the drug used, with ajmaline more likely to provoke a type 1 Brugada electrocardiographic pattern compared with procainamide. Patients undergoing SCB challenge may have contrasting results depending on the drug used, with potential clinical, psychosocial, and socioeconomic implications.

The Brugada syndrome (BrS) is a hereditary arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals without overt structural heart disease. Currently, its diagnosis is mainly based on the presence of a spontaneous or Na+-channel blocker induced so-called “type 1” Brugada electrocardiographic (ECG) pattern typically seen in leads V1 and V2 recorded from the 4th to 2nd intercostal spaces. Presently the main unresolved clinical problem in the BrS is the identification of patients at high risk of SCD who need implantable cardioverter-defibrillator (ICD). Current guidelines recommend ICD implantation only in patients with spontaneous type 1 ECG pattern and either history of aborted cardiac arrest or documented sustained ventricular tachycardia (class I) or syncope of arrhythmic origin (class IIa) because they are at high risk of recurrent arrhythmias. However, the majority of BrS patients are asymptomatic when diagnosed and have generally low risk (0.5 % annually or lower) and therefore are not indicated for ICD. Most of SCD victims in the BrS have had no symptoms prior to the fatal event and therefore were not protected with an ICD. Currently there are no reliable methods to identify these potential victims of SCD. Although some ECG markers such as QRS fragmentation and infero-lateral early repolarisation have been demonstrated to signify increased arrhythmic risk their value still needs to be confirmed in large prospective studies. Novel risk assessment strategies need to be developed based on computerised quantitative ECG analysis of large digital ECG databases in patients with BrS and their relatives, and combined assessment of the most important factors of ventricular arrhythmogenesis.

The formulation of the syndrome of interatrial conduction block is an important step for improved identification of patients at high risk of developing atrial fibrillation (those with advanced, that is, third degree interatrial block, which includes retrograde instead of normal activation of the left atrium). The rationale and potential benefits of prophylactic antiarrhythmic treatment of patients with advanced interatrial block currently seems not sufficiently convincing and requires further study including prospective trials. In addition to the identified future directions for research in this syndrome, it seems important also to explore novel electrocardiogram (ECG) methods (e.g. new electrode positions and ECG leads) for improved characterisation of the atrial electrical events. Oesophageal electrocardiography and vectorcardiography are old, venerable and unjustifiably forgotten ECG techniques: their additional use of for better diagnosis of interatrial conduction block is highly commendable.

The standard 12-lead electrocardiogram (ECG) is only one of the possible ways to present the voltage differences between the nine recording electrodes. Other “non-conventional” leads may be constructed by physically connecting two or more electrodes in a different manner or by computation from the digital 12-lead ECG. Examples include bipolar or multipolar precordial leads and bipolar chest leads (between one precordial and one limb electrode). Such leads can remove or decrease noise originating from a limb cable/electrode that is present in the unipolar precordial leads. They can be diagnostically useful in Brugada syndrome and can display QRS fractionation that is not visible in the respective unipolar precordial or limb leads. Multipolar precordial leads sometimes display potentially useful information that is not visible in the respective unipolar leads and in bipolar leads computed from them. In conclusion, these computed ECG leads represent a potentially useful supplement to the conventional 12-lead ECG.

Aims The aims of this study were three-fold and were to (i) investigate the effect of food (fasted and fed state) on the degree of QT prolongation caused by moxifloxacin under the rigorous conditions of a TQT study, (ii) differentiate the effects on QTc that arise from changes in PK from those arising as a result of electrophysiological changes attributable to raised levels of C-peptide [11] offsetting in part the IKr blocking properties of moxifloxacin and (iii) characterize the QTcF profile of oral moxifloxacin (400 mg) in healthy Japanese volunteers compared with Caucasian subjects. Methods The study population consisted of 32 healthy non-smoking, Caucasian (n = 13) and Japanese (n = 19), male and female subjects, aged between 20–45 years with a body mass index of between 18 to 25 kg m−2. Female volunteers were required to use an effective contraceptive method or be abstinent. Subjects with ECGs which were deemed unsuitable for evaluation in a TQT study were excluded. ECGs were recorded in triplicate with subsequent blinded manual adjudication of the automated interval measurements. Electrocardiograms in the placebo arm were recorded twice in fasted and fed condition. Results The results demonstrated a substantial change in the typical moxifloxacin effect on the ECG. The effect on ΔΔQTc in the fed state led to a significant delay and a modest reduction compared with the fasted state correcting both conditions with the corresponding placebo data. The largest QTcF change from baseline in the fed state was observed at 4 h with a peak value of 11.6 ms (two-sided 90% CI 9.1, 14.1). In comparison, the largest QTcF change observed in the fasted state was 14.4 ms (90% CI 11.9, 16.8) and occurred at 2.5 h post-dose. The PK of moxifloxacin were altered by food and this change was consistent with the observed QTcF change. In the fed state plasma concentrations of moxifloxacin were considerably and consistently lower in comparison with the fasted state, and this applied to both ethnicities. The concentration–effect analysis revealed that there was no change in slope and confirmed that the difference in this analysis was caused by a change in the PK profile of moxifloxacin. Comparisons of the moxifloxacin effect in the fed state compared with fasted placebo also revealed a pharmacodynamic effect whereby a meal appears to antagonize the effects of moxifloxacin on the lengths of the QTc interval. Conclusions Our findings demonstrate that the food effect by itself leads to a shortening of the QTc interval offsetting in part the effects of a 400 mg single dose of oral moxifloxacin. The typical moxifloxacin PK profile is also altered by food prior to dosing reducing the Cmax and delays the peak effects on QTc up to several hours thereby reducing the overall magnitude of the effect and delaying the peak QTc prolongation. The contribution of the two effects was clearly discernible. Given that moxifloxacin is sometimes given with food in TQT studies, consideration should be given to adequate baseline corrections and appropriate sampling time points. In this study the PK–PD relationship was similar for Japanese and Caucasian subjects in the fed and fasted conditions, thereby providing further evidence that the sensitivity to the QTc prolonging effects of fluoroquinolones was likely to be independent of ethnicity. The small differences observed between the two subpopulations were not statistically significant. However, future studies should give consideration to formal ethnic comparisons as a secondary outcome parameter as very little is known about the relationship between ethnicity and drug effects on cardiac repolarization.

Early repolarization (ER) in the inferior electrocardiogram leads is associated with idiopathic ventricular fibrillation, but the majority of subjects with ER have a benign prognosis. At present, there are no risk stratifiers for asymptomatic ER.To examine the response to ajmaline provocation and exercise in potentially high-risk subjects with ER and without a definitive cardiac diagnosis.Electrocardiographic data were reviewed for ER at baseline and during ajmaline and exercise testing in 229 potentially high-risk patients (mean age 37.7±14.9 years; 55.9% men). ER was defined as J-point elevation in ≥2 consecutive leads and stratified by type, territory, J-point height, and ST-segment morphology.Baseline ER was present in 26 (11.4%; 19 men) patients. During ajmaline provocation and exercise, there were no new ER changes. ER with rapidly ascending ST-segment and lateral ER consistently diminished. There were 7 patients with persistent ER during ajmaline and/or exercise. They were all men with inferior or inferolateral ER and horizontal/descending ST segment. Those with persistent ER during exercise were more likely to have a history of unexplained syncope than those in whom ER changes diminished (P.01). Subtle nondiagnostic structural abnormalities were demonstrated in 3 of these patients.ER with horizontal/descending ST-segment morphology in the inferior or inferolateral leads that persists during exercise is more common in patients with prior unexplained syncope and may identify patients at higher risk of arrhythmic events. ER that persists during ajmaline provocation and/or exercise may reflect underlying subtle structural abnormalities and should prompt further investigation.

Aims Food is known to shorten the QTc (QTcI and QTcF) interval and has been proposed as a non-pharmacological method of confirming assay sensitivity in thorough QT (TQT) studies and early phase studies in medicines research. Intake of food leads to a rise in insulin levels together with the release of C-peptide in equimolar amounts. However, it has been reported that euglycaemic hyperinsulinemia can prolong the QTc interval, whilst C-peptide has been reported to shorten the QTc interval. Currently there is limited information on the effects of insulin and C-peptide on the electrocardiogram (ECG). This study was performed to assess the effect of insulin, glucose and C-peptide on the QTc interval under the rigorous conditions of a TQT study. Methods Thirty-two healthy male and female, Caucasian and Japanese subjects were randomized to receive six treatments: (1) placebo, (2) insulin euglycaemic clamp, (3) carbohydrate rich ‘continental’ breakfast, (4) calorie reduced ‘American’ FDA breakfast, (5) moxifloxacin without food, and (6) moxifloxacin with food. Measurements of ECG intervals were performed automatically with subsequent adjudication in accordance with the ICH E14 guideline and relevant amendments. Results No effect was observed on QTcF during the insulin euglycaemic clamp period (maximal shortening of QTcF by 2.6 ms, not significant). Following ingestion of a carbohydrate rich ‘continental’ breakfast or a calorie reduced ‘American’ FDA standard breakfast, a rapid increase in insulin and C-peptide concentrations were observed. Insulin concentrations showed a peak response after the ‘continental’ breakfast observed at the first measurement time point (0.25 h) followed by a rapid decline. Insulin concentrations observed with the ‘American’ breakfast were approximately half of those seen with the ‘continental’ breakfast and showed a similar pattern. C-peptide concentrations showed a peak response at the first measurement time point (0.25 h) with a steady return to baseline at the 6 h time point. The response to the ‘continental’ breakfast was approximately double that of the ‘American’ FDA breakfast. A rapid onset of the effect on QTcF was observed with the ‘continental’ breakfast with shortening by >5 ms in the time interval from 1 to 4 h. After the ‘American’ FDA breakfast, a similar but smaller effect was seen. Conclusions The findings of this study demonstrate that there was no change in QTc during the euglycaemic clamp. Given that insulin was raised to physiological concentrations comparable with those seen after a meal, whilst the release of C-peptide was suppressed, insulin appears to have no effect on the QTc interval in either direction. The results suggest a relationship exists between the shortening of QTc and C-peptide concentrations and indicate that glucose may have a QTc prolonging effect, which will require further research.

Background: Right precordial (V1–3) elevated electrode placement ECG (EEP-ECG) is often used in the diagnosis of Brugada syndrome (BrS). However, the specificity of this has only been studied in smaller studies in Asian populations. We aimed to study this in a larger European population. Methods: Two different populations consisting of healthy subjects were used. A total of 340 subjects were included, 80% were men, the median age was 43 year (interquartile range: 31–51) and all were of European ethnicity. Results: No type 1 ECG patterns were identified but 16 (4.7%) subjects with a type 2 ECG and 32 (9.4%) subjects with a type 3 ECG were identified in any lead placement. In total 43 (13%) subjects had any BrS ECG pattern in any lead placement. The specificity was 100% (one-sided 97.5% CI: 99%) for the use of EEP-ECG to uncover type 1 pattern. For type 2 pattern the specificity was 95% (95% CI: 92–97%) and for type 3 pattern 91% (95% CI: 88–94%). Conclusions: Elevated electrode placement ECG in the diagnosis of BrS seems to have a very high specificity with regards to the finding of a type 1 ECG pattern in a European population; conversely a finding of a type 2 or 3 pattern is of a significantly lower specificity and should perhaps be disregarded.

Background: Epidemiological data suggest increased risk of sudden death during and immediately after hemodialysis. Microvolt T-wave alternans (mTWA) is an electrocardiogram (ECG) measure of abnormal ventricular repolarization, which can be used in sudden death risk stratification. The aim of this study was to determine whether mTWA measurements during dialysis indicate abnormal repolarization as a potential trigger to dialysis associated arrhythmias. Methods: Forty-eight-hour, 12-lead Holter ECG recordings were taken on a cohort of maintenance hemodialysis patients. Modified moving average mTWA was examined for 48 hours from the start of dialysis. Predialysis biochemistry was taken and echocardiography was performed on a nondialysis day. Results: Nineteen patients were analyzed (age 61 ± 14 years, time on dialysis 2.7 ± 2 years). mTWA increased during dialysis (P < 0.01) but returned to baseline 2 hours postdialysis (first hour mTWA = 10.1 ± 4.5μV, final hour mTWA = 12.2 ± 3.7μV, postdialysis mTWA = 10.3 ± 2.7μV, P = 0.015). The change in mTWA did not correlate with serum biochemistry or echocardiographic measurements of left ventricular mass and function. Peak mTWA and frequency of spikes in mTWA ≥ 65μV were not more common during dialysis compared to other times. Patients who showed greater frequency of spikes ≥65μV or increase in hourly mean mTWA during dialysis did not have a worse cardiovascular outcome over a mean follow-up of 2.6 years. Conclusions: Though there were subtle changes in mTWA during dialysis, there was no association with mTWA abnormalities previously shown to be associated with worse outcome. The presence of abnormal mTWA did not correlate with outcome. (PACE 2012; 35:703–710)

Opinion has oscillated in the cardiology community regarding the significance of ventricular premature beats and non-sustained ventricular tachycardia as predictors of sudden cardiac death. Automaticity can be a marker of underlying structural heart disease. It is unclear whether the apparent association with sudden death is simply a reflection of this fact. Older data are unreliable as the populations studied probably had a high prevalence of unrecognized structural heart disease. Current risk stratification is imperfect. The balance of evidence suggests that automaticity does predict risk and it may have a role in risk-assessment algorithms, but at present the dataset is insufficient.

Aims Sporadic cases have reported the coexistence of coronary spasm and Brugada syndrome. However, the prevalence of the Brugada phenotype in coronary spasm is unknown, particularly in non-Japanese populations. In this study, we sought to examine the prevalence of the type 1 Brugada electrocardiogram (ECG) in a large European patient population undergoing intracoronary provocation testing for suspected coronary spasm. Methods and results We retrospectively evaluated ECG data for the presence of type 1, 2, and 3 Brugada ECGs from 955 consecutive German patients without obstructive coronary artery disease undergoing intracoronary acetylcholine (ACH) provocation (ACH-test). Eight hundred and twenty-seven patients (age 63 ± 12 years; 42% male) with complete ECG data were eligible for further analysis. The ACH-test revealed coronary spasm in 325 patients (39.3%). A Brugada ECG of any type was found in six patients (0.7%) at baseline and eight patients (0.9%) at any time. There was no difference in the prevalence of coronary spasm in patients with (37.5%) and without (39.3%) Brugada-type ECGs. The type 1 Brugada ECG was not seen at baseline, but two type 1 Brugada ECGs were observed during ACH-administration into the right coronary artery (RCA; 0.2%), one with simultaneous RCA spasm and one without. Ajmaline provocation testing reproduced the type-1 Brugada ECG in the patient without coronary spasm but she had no other features of the Brugada syndrome. Conclusions This study reports a low prevalence of the type 1 Brugada ECG in the largest known European collection of intracoronary ACH provocation. In these patients, we found no evidence for the coexistence of Brugada syndrome and coronary spasm. This is in contrast to available Japanese data.

Background: Previous studies have shown conflicting results about the value of heart rate turbulence (HRT) for risk stratification of patients (pts) with chronic heart failure (CHF). We prospectively evaluated the relation between HRT and progression toward end-stage heart failure or all-cause mortality in patients with CHF. Methods: HRT was assessed from 24-hour Holter recordings in 110 pts with CHF (54 in NYHA class II, 56 in class III–IV; left ventricular ejection fraction (LVEF) 30%± 10%) on optimal pharmacotherapy and quantified as turbulence onset (TO,%), turbulence slope (TS, ms/RR interval), and turbulence timing (beginning of RR sequence for calculation of TS, TT). TO ≥ 0%, TS ≤ 2.5 ms/RR, and TT >10 were considered abnormal. End point was development of end-stage CHF requiring heart transplantation (OHT) or all-cause mortality. Results: During a follow-up of 5.8 ± 1.3 years, 24 pts died and 10 required OHT. TO, TS, TT, and both (TO and TS) were abnormal in 35%, 50%, 30%, and 25% of all patients, respectively. Patients with at least one relatively preserved HRT parameter (TO, TS, or TT) (n = 98) had 5-year event-free rate of 83% compared to 33% of those in whom all three parameters were abnormal (n = 12). In multivariate Cox regression analysis, the most powerful predictor of end point events was heart rate variability (SDNN < 70 ms, hazard ratio (HR) 9.41, P < 0.001), followed by LVEF ≤ 35% (HR 6.23), TT ≥ 10 (HR 3.14), and TO ≥ 0 (HR 2.54, P < 0.05). Conclusion: In patients with CHF on optimal pharmacotherapy, HRT can help to predict those at risk for progression toward OHT or death of all causes. Ann Noninvasive Electrocardiol 2010;15(3):230–237

Background Leads V 1 and V 2 recorded from the standard position (fourth intercostal space) have insufficient sensitivity to detect the diagnostic type 1 Brugada ECG pattern. Objective The purpose of this study was to compare the sensitivity of bipolar leads with a positive pole at V 2 and a negative pole at V 4 or V 5 with that of the standard unipolar lead V 2 for detection of the type 1 Brugada pattern. Methods We analyzed digital 15-lead ECGs (12 standard leads plus leads V 1 to V 3 recorded from the third intercostal space [V 1h to V 3h ]) acquired during diagnostic ajmaline testing in 128 patients (80 men, age 37 ± 15 years) with suspected Brugada syndrome and standard 12-lead ECGs recorded in 229 healthy subjects (111 men, age 33 ± 4 years). Bipolar leads between V 2 (positive pole) and V 4 or V 5 (leads V 2–4 , V 2–5 ) were derived by subtracting leads V 4 and V 5 from V 2 . All ECGs were examined for the presence of type 1 Brugada pattern. Results During 21 (16.4%) positive ajmaline tests, type 1 pattern was observed in lead V 2h during 20 tests (95.2%) and in V 2 during 10 tests (47.6%). Type 1 pattern appeared in lead V 2–4 or V 2–5 in all tests when it was present in V 2 and in seven tests during which it was observed in lead V 2h but not V 2 (17 tests [81%]). Type 1–like pattern was observed in lead V 2–4 or V 2–5 during two nonpositive tests (1.9%) and in one healthy subject (0.4%). Conclusion Bipolar leads V 2–4 and V 2–5 are more sensitive than lead V 2 for detection of the type 1 Brugada pattern.

In addition to knowledge of normal and pathological patterns, the correct interpretation of electrocardiographic (ECG) recordings requires the use of acquisition procedures according to approved standards. Most manuals on standard electrocardiography devote little attention to inadequate ECG recordings. In this article, we present the most frequent ECG patterns resulting from errors in limb and precordial lead placement, artifacts in 12‐lead ECG as well as inadequate filter application; we also review alternative systems to the standard ECG, which may help minimize errors.

Background Current consensus documents on Brugada syndrome recommend the diagnostic intravenous administration of a Na-channel blocker to be stopped when the QRS prolongs to ≥130% of baseline, presumably because of increased arrhythmic risk. Objective This study sought to assess QRS prolongation during ajmaline testing and its relation to arrhythmic risk. Methods We analyzed an electrocardiographic (ECG) database collected during ajmaline testing in 148 patients (92 men, age 36 ± 15 years). The QRS was measured at baseline and during the 1st to 7th, 10th, and 15th minute after the beginning of ajmaline administration. Results The average QRS prolongation was 36% ± 16% (range 9% to 88%), not significantly different between positive (n = 30) and negative (n = 118) tests. QRS prolonged to ≥130% during 16 (55%) positive and 71 (61%) negative tests ( P = .50), with no clinical side effects. The incidence of ventricular arrhythmias was not significantly different between patients with and without QRS prolongation. Short runs (3 to 8 complexes) of nonsustained ventricular tachycardia occurred in 3 patients with QRS prolongation ≥130%. In 40% of positive tests, prolongation ≥130% occurred earlier by >1 minute than diagnostic Brugada ECG changes, i.e., early termination of the test could possibly have resulted in false-negative outcomes. Conclusion QRS prolongation ≥130% occurs in >50% of all tests. In 40% of positive tests it occurs before diagnostic ECG changes. Always terminating the test when QRS prolongs ≥130% could possibly result in loss of important diagnostic information. It is appropriate to adjust the criteria for early termination of the test to the baseline QRS and possibly other factors.

We tested the hypothesis that ventricular repolarization of the first sinus beat following a ventricular premature beat (VPB) can be modulated in the absence of clearly discernible T-wave changes. We applied principal component analysis (PCA) to assess QRS and T-wave complexity of sinus beats preceding and following VPBs in multiple 10-second resting 12-lead electrocardiograms of two subjects with frequent VPBs and no apparent heart disease. In both subjects, T-wave complexity of the first post-VPB beat was significantly increased compared to the beats preceding the VPB.

Background The ventricular ectopic QRS interval (VEQSI) has been shown to identify structural heart disease and predict mortality. In arrhythmogenic right ventricular cardiomyopathy (ARVC), early diagnosis is difficult using current methods, and life-threatening arrhythmias are common and difficult to predict. Objective The purpose of this study was to assess the utility of ventricular ectopic indices including VEQSI in ARVC diagnosis. Methods We studied 70 patients with ARVC [30 with definite disease (age 47 ± 12 years; 60% male), 40 with incomplete disease expression (age 44 ± 18 years; 44% male)], 116 healthy controls (age 40 ± 15 years; 56% male), and 26 patients with normal heart right ventricular outflow tract (RVOT) ectopy (age 46 ± 17 years; 27% male). The duration of the broadest ventricular ectopic beat during 12-lead Holter monitoring was recorded as VEQSI max. Results VEQSI max was associated with age and gender, but not with conducted QRS duration. Adjusted VEQSI max was greater in ARVC patients than in control groups. In healthy males (44.5 years), estimated VEQSI max was 163 ms (95% confidence interval [CI] 159–167 ms); in definite ARVC 212 ms (95% CI 206–217 ms); in incompletely expressed ARVC 204 ms (95% CI 199–210 ms); and in normal heart RVOT ectopy 171 ms (95% CI 165–178 ms). VEQSI max >180 ms had 98% sensitivity and specificity for diagnosis of ARVC (area under the curve 0.99, 95% CI 0.980–0.998). In our incompletely expressed ARVC patients, VEQSI max >180 ms identified 88% as affected. Conclusion VEQSI max distinguishes ARVC patients, including those with incomplete disease expression, from healthy controls and patients with normal heart RVOT ectopy.

Aims: In order to improve the electrocardiographic (ECG) diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC), we evaluated novel quantitative parameters of the QRS complex and the value of bipolar chest leads (CF leads) computed from the standard 12 leads.\ud Methods and results: We analysed digital 12-lead ECGs in 44 patients with ARVC, 276 healthy subjects including 44 age and sex-matched with the patients and 36 genotyped members of ARVC families. The length and area of the terminal S wave in V1 to V3 were measured automatically using a common for all 12 leads QRS end. T wave negativity was assessed in V1 to V6 and in the bipolar CF leads computed from the standard 12 leads. The length and area of the terminal S wave were significantly shorter, whereas the S wave duration was significantly longer in ARVC patients compared with matched controls. Among members of ARVC families, those with mutations (n = 15) had shorter QRS length in V2 and V3 and smaller QRS area in lead V2 compared with those without mutations (n = 20). In ARVC patients, the CF leads were diagnostically superior to the standard unipolar precordial leads. Terminal S wave duration in V1 >48 ms or major T wave negativity in CF leads separated ARVC patients from matched controls with 90% sensitivity and 86% specificity.\ud Conclusion: The terminal S wave length and area in the right precordial leads are diagnostically useful and suitable for automatic analysis in ARVC. The CF leads are diagnostically superior to the unipolar precordial leads.

The costs of clinical investigations of drug-induced QT interval prolongation are mainly related to manual processing of electrocardiographic (ECG) recordings. Potentially, however, these costs can be decreased by automatic ECG measurement. To investigate the improvements in measurement accuracy of the modern ECG equipment, this study investigated QT interval measurement by the "old" and "new" versions of the 12SL ECG algorithm by GE Healthcare (Milwaukee, WI, USA) and compared the results to carefully validated and reconciled manual measurements. The investigation used two sets (A and B) of ECG recordings that originated from large clinical studies. Sets A and B consisted of 15,194, and 29,866 10-second ECG recordings, respectively. All the recordings were obtained with GE Healthcare recorders and were available in digital format compatible with ECG processing software by GE Healthcare. The two sets of recordings differed significantly in ECG quality with set B being substantially more noise polluted. Compared to careful manual QT interval readings in recording set A, the errors of the automatic QT interval measurement were (mean +/- SD) +3.95 +/- 5.50 ms, and +0.51 +/- 12.41 ms for the "new" and "old" 12SL algorithm, respectively. In recording set B, these numbers were +2.41 +/- 9.47 ms, and -0.17 +/- 14.89 ms, respectively (both differences were highly statistically significant, P < 0.000001). In recording set A, 95.9% and 76.6% of ECGs were measured automatically within 10 ms of the manual measurement by the "new" and "old" versions of the 12SL algorithm, In recording set B, these numbers were 83.9% and 59.5%. The errors made by the "new" and "old" version of 12SL algorithm were practically independent each of the other (correlation coefficients of 0.031 and 0.281 in recording sets A and B, respectively). The study shows that (a) compared to the "old" version of the 12SL algorithm, the QT interval measurement by the "new" version implemented in the most recent ECG equipment by GE Healthcare is significantly better, and (b) the precision of automatic measurement by the 12SL algorithm is substantially dependent on the quality of processed ECG recordings. The improved accuracy of the "new" 12SL algorithm makes it feasible to use modern ECG equipment without any manual intervention in selected parts of drug-development program.

Regulatory authorities require new drugs to be investigated using a so-called "thorough QT/QTc study" to identify compounds with a potential of influencing cardiac repolarization in man. Presently drafted regulatory consensus requires these studies to be powered for the statistical detection of QTc interval changes as small as 5 ms. Since this translates into a noticeable drug development burden, strategies need to be identified allowing the size and thus the cost of thorough QT/QTc studies to be minimized. This study investigated the influence of QT and RR interval data quality and the precision of heart rate correction on the sample sizes of thorough QT/QTc studies. In 57 healthy subjects (26 women, age range 19-42 years), a total of 4,195 drug-free digital electrocardiograms (ECG) were obtained (65-84 ECGs per subject). All ECG parameters were measured manually using the most accurate approach with reconciliation of measurement differences between different cardiologists and aligning the measurements of corresponding ECG patterns. From the data derived in this measurement process, seven different levels of QT/RR data quality were obtained, ranging from the simplest approach of measuring 3 beats in one ECG lead to the most exact approach. Each of these QT/RR data-sets was processed with eight different heart rate corrections ranging from Bazett and Fridericia corrections to the individual QT/RR regression modelling with optimization of QT/RR curvature. For each combination of data quality and heart rate correction, standard deviation of individual mean QTc values and mean of individual standard deviations of QTc values were calculated and used to derive the size of thorough QT/QTc studies with an 80% power to detect 5 ms QTc changes at the significance level of 0.05. Irrespective of data quality and heart rate corrections, the necessary sample sizes of studies based on between-subject comparisons (e.g., parallel studies) are very substantial requiring >140 subjects per group. However, the required study size may be substantially reduced in investigations based on within-subject comparisons (e.g., crossover studies or studies of several parallel groups each crossing over an active treatment with placebo). While simple measurement approaches with ad-hoc heart rate correction still lead to requirements of >150 subjects, the combination of best data quality with most accurate individualized heart rate correction decreases the variability of QTc measurements in each individual very substantially. In the data of this study, the average of standard deviations of QTc values calculated separately in each individual was only 5.2 ms. Such a variability in QTc data translates to only 18 subjects per study group (e.g., the size of a complete one-group crossover study) to detect 5 ms QTc change with an 80% power. Cost calculations show that by involving the most stringent ECG handling and measurement, the cost of a thorough QT/QTc study may be reduced to approximately 25%-30% of the cost imposed by the simple ECG reading (e.g., three complexes in one lead only).

Department of Cardiac and Vascular Sciences, St. George’s Hospital Medical School, London, EnglandSummaryBackground: The expansion of indications for implanta-tion of cardioverter-defibrillators (ICD) has enhanced theneed for risk stratification of patients post myocardial infarc-tion (MI), while the improved treatment of acute MI has de-creased mortality and diminished the prognostic power of tra-ditional risk variables.Hypothesis: Increased heterogeneity of ventricular repo-larization quantified by TCRT (total cosine R-to-T, angulardifference between spatial QRS and T loops, decreased withincrease in repolarization heterogeneity) is an independentpredictor of mortality in patients post MI.Methods: Left ventricular ejection fraction (EF), QRS du-ration on signal-averaged ECG, number of ventricular ec-topic beats (VE)/h, heart rate variability (HRV) triangular in-dex, heart rate turbulence slope on 24-h Holter recording, andTCRT were analyzed in 334 survivors of acute MI followedup for 41 ±20 months.Results: In multivariate analysis, EF 10/h (RR 2.2, CI 1.0–4.6, p = 0.044), HRV 60 and >30%, respectively, compared with 17 and 7% in those with only EF

Present experience with prospective identification of patients who might benefit from prophylactic antiarrhythmic intervention is restricted to risk stratification using left ventricular ejection fraction (LVEF). The precision of LVEF-based identification of high risk patients is neither highly sensitive nor highly specific. This study investigated risk stratification of 466 survivors of acute myocardial infarction (86 women, mean age 57.5 years) for whom a 5-year follow-up was available. During the follow-up 67 patients died and 24 of these events were sudden arrhythmic deaths. In addition to LVEF, patients were stratified by mean heart rate, heart rate variability and the slope of heart rate turbulence, all derived from 24-hour Holter recording obtained before hospital discharge, and by the 3D angle between QRS complex and T wave vectors (total cosine R-to-T, TCRT) obtained from digital resting electrocardiogram before hospital discharge. Individual risk characteristics and their combinations were evaluated by calculating the areas under the receiver operator characteristics (ROC). The bootstrap technology was used to investigate these statistically. For the stratification of both all cause mortality and sudden arrhythmic death, TCRT was the strongest risk stratifier (area under ROC of 0.6857 +/- 0.0367, and 0.7275 +/- 0.0544, respectively) that compared very favourably to LVEF (area under the ROC of 0.6610 +/- 0.0362 and 0.6346 +/- 0.0595, for all cause and arrhythmic death prediction, both P < 10(-10) for the comparison with TCRT). TCRT was also stronger in combination with other stratifiers, eg, TCRT + LVEF (area under ROC of 0.7631 +/- 0.0325 and 0.8057 +/- 0.0473, for all cause and arrhythmic death prediction) was stronger than mean heart rate + LVEF (area under ROC of 0.7396 +/- 0.0298 and 0.7673 +/- 0.0445, respectively, both P < 10(-10) for comparison with TCRT + LVEF). Hence the 3D QRS-T angle is a very powerful risk stratifier especially suited for the prediction of sudden arrhythmic death. It should be prospectively investigated in future trials of prophylactic antiarrhythmic interventions.

A computational study was designed to investigate the differences between the so-called study-specific and subject-specific heart rate corrections of QT interval. In 53 healthy subjects (25 women, mean age 26.7 ± 8.7 years), serial 10-second electrocardiograms (ECG) were obtained during daytime hours. In each subject, 200 ECGs were selected representative of the individual QT/RR relationship. Of the population of 53 subjects, 30,000 different subgroups of 16 subjects were considered and their data used to model drug induced QT interval prolongation by 0, 5, 10, and 20 ms combined with drug induced heart rate acceleration and deceleration. In each modeled study, QTc changes were assessed by: (1) Six study-specific heart rate corrections designed by regression modeling of the baseline QT/RR data pooled from all subjects; (2) Six subject-specific heart rate corrections designed by the same regression modeling of the baseline QT/RR data in each subject separately; (3) subject optimized correction that selected the best fitting regression model for each individual; and (4) by Bazett and Fridericia corrections. In each modeled study, the errors of the correction approaches were estimated and statistically summarized over all modeled studies. The subject-specific corrections led to maximum errors in single milliseconds (error range of 2.4, 5.7, and 2.6 ms with linear, log/log linear, and exponential models, respectively) while the study-specific corrections led to substantially greater errors (error range of 17.8, 19.4, and 16.9 ms with linear, log/log linear, and exponential models, respectively). Both Bazett and Fridericia corrections led not only to substantial errors (error range of 28.3 and 16.9 ms) but also to regular bias with systematically false negative and false positive conclusions dependent on modeled heart rate acceleration and deceleration. Thus, subjects-specific corrections should be used in the intensive and definite studies aimed at providing the final answer on the ability of a drug to prolong the QT interval. (PACE 2004; 27[Pt. I]:791–800)

Comparing patients treated after myocardial infarction with amiodarone or with placebo, we found a significant rate-dependent prolongation of TpTe interval in patients who received amiodarone. Patients who had arrhythmic death had significantly longer TpTe intervals than others on placebo but not on amiodarone. Assuming that TpTe reflects transmural repolarization heterogeneity, our findings suggest that heterogeneity and arrhythmic risk are increased by amiodarone. This contradicts the finding of decreased transmural repolarization heterogeneity by amiodarone and the appreciated antiarrhythmic efficacy of this drug.

Objective: The interval from the peak to the end of the T wave (TpTe) has been proposed to reflect the heterogeneity of action potential durations within the ventricular wall. Several studies have previously described TpTe to be independent of heart rate, which contradicts the in vitro observation of marked changes in transmural repolarisation heterogeneity due to cycle length changes. Because of this inconsistency, we investigated heart rate related changes of TpTe interval. Methods: During 24-h recordings (SEER MC, Marquette GE) in healthy young women ( n = 25, 26±7 years) and men ( n = 25, 27±8 years), a 10-s 12-lead ECG was obtained every 30 s. Recordings were repeated after 1 day, 1 week, and 1 month and results in each subject were pooled together and grouped for women and men. The QT and QTpeak intervals were obtained automatically using QT Guard software (Marquette) and TpTe was computed as the difference between QT and QTpeak. In each subject TpTe values were averaged over 10-ms RR interval bands from 550 to 1150 ms. Results: In both sexes, TpTe interval showed marked rate dependence with prolongation at long RR intervals. TpTe intervals in men were significantly longer over the entire range of investigated RR intervals ( P = 1.4×10−25). However, whereas the difference between sexes was marked at short cycle length (RR interval bin 540–550 ms: women 87±5 vs. men 95±9, P = 5.1×10−4) it decreased at long cycle lengths (RR interval bin 1140–1150 ms: women 99±5 vs. men 106±6, P = 9.3×10−4). Conclusion: There is a marked rate dependence of TpTe interval, which differs between women and men. The finding is consistent with the TpTe interval being an approximate surrogate of the intraventricular repolarisation gradient. The rate dependent increase in transmural repolarisation heterogeneity might be one of the reasons for the increased propensity of torsades de pointes in women.

A reduced circadian pattern in the QTc interval has been repeatedly reported to provide prognostic information in cardiac patients. However, the results of studies in healthy subjects in which different heart rate correction formulas were used are inconsistent regarding the presence and extent of diurnal variations in QTc. This study compared the diurnal variations in QTc obtained with four frequently used heart rate correction models with those based on individually optimized heart rate correction. In 53 subjects (25 men aged 27 +/- 7 years and 28 women aged 27 +/- 9 years) 12-lead digital ECGs were obtained every 30 seconds during 24 hours. The QT interval was measured automatically by six different algorithms provided by a commercially available device. The QT/RR relation was estimated by four common heart rate correction models and by an individually optimized correction model, QTc = QT/RR alpha. In each 24-hour recording, RR, QT, and WTc intervals of separate ECG samples were averaged over 10-minute intervals. Marked differences were found in the extent of the circadian pattern of QTc obtained with different formulas for heart rate correction. Under and overcorrection of the QT interval resulted in significant over- or underestimation of the circadian pattern. Thus, the extent of circadian variation in QTc depends highly on the heart rate correction formula used. To obtain proper insight regarding diurnal variation in QTc prolongation during pharmacologic therapy and/or to assess higher risk due to impaired autonomic regulation of ventricular repolarization, individualized heart rate correction is necessary.

Background: Total R T cosine (TCRT) is a new descriptor of repolarization heterogeneity that quantifies the deviation between the directions of ventricular depolarization and repolarization. It revives the old concept of ventricular gradient (VG). Hypothesis: Our goal was to examine whether TCRT and VG contain nonredundant information by comparing their reaction to autonomic tests, namely, postural changes and Valsalva maneuver. Methods: Digital 12-lead electrocardiograms were recorded in 16 patients with cardiovascular syndrome X (SX, chest pain, exercise-induced ST-depression, normal coronary arteries, 3 men, age 60 ± 9 years) and 40 healthy volunteers (31 men, age 33 ± 7 years) during postural changes and Valsalva maneuver. The angle (VGA) [°] and magnitude (VGM) [ms.mV] of VG in reconstructed XYZ leads and TCRT (average cosine of the angles between the QRS and T vectors in mathematically reconstructed three-dimensional space) were calculated. Results: (mean ± standard of the mean): In healthy subjects, VGM and TCRT decreased, whereas VGA increased in the sitting and standing compared with supine position (TCRT: 0.61 ± 0.05, 0.47 ± 0.06, 0.29 ± 0.08, supine, sitting, and standing, p < 0.05) and during phase II Valsalva (TCRT: 0.47 ± 0.06 vs. 0.61 ± 0.05, p < 0.01 in supine, 0.24 ± 0.08 vs. 0.37 ± 0.07, p < 0.01 in standing). In patients with SX, VGM decreased in the standing position, VGA did not change significantly, while TCRT decreased only in patients without T-wave abnormalities (n = 9) (TCRT in standing and supine: 0.55 ± 0.09 vs. 0.68 ± 0.08, p < 0.05). VGM increased during Valsalva in patients with SX. Total R T cosine correlated strongly with VGA (r = –0.84, p< 0.00001) and, unlike VGM, did not correlate with heart rate. Conclusions: Ventricular gradient and TCRT contain non-redundant information. In healthy subjects, they react sensitively to autonomic provocation. In patients with SX, their reaction is attenuated, which suggests disturbance of the autonomic control of repolarization.

In clinical practice, an imprecision introduced by ad hoc selected heart rate correction formula of the QTinterval is unlikely to lead to erroneous conclusions if all borderline cases are carefully considered. On thecontrary, in clinical investigations (e.g., studies of drug effects) the over- or undercorrection of QTcmay lead to significant and systematic bias with both false positive and false negative findings. None of the previously published “global” heart rate correction formulae has been universallysuccessful because the QT/RR relationship is different between different subjects and a formula that correctsthe QT interval for heart rate acceptably in one individual may be very misleading in another individual.Moreover, it has been recently established that the QT/RR patterns not only exhibit a substantialinter-subject variability but also a high intra-subject stability. Thus, in precise investigations, individualQT/RR relationship should be first established in each subject and subsequently translated into individualheart rate correction formula.

The Brugada syndrome (BrS) is a malignant, genetically-determined, arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals with structurally normal hearts. The diagnosis of the BrS is mainly based on the presence of a spontaneous or Na+channel blocker induced characteristic, electrocardiographic (ECG) pattern (type 1 or coved Brugada ECG pattern) typically seen in leads V1 and V2 recorded from the 4th to 2nd intercostal (i.c.) spaces. This pattern needs to be distinguished from similar ECG changes due to other causes (Brugada ECG phenocopies). This review focuses mainly on the ECG-based methods for diagnosis and arrhythmia risk assessment in the BrS. Presently, the main unresolved clinical problem is the identification of those patients at high risk of SCD who need implantable cardioverter-defibrillator (ICD), which is the only therapy with proven efficacy. Current guidelines recommend ICD implantation only in patients with spontaneous type 1 ECG pattern, and either history of aborted cardiac arrest or documented sustained VT (class I), or syncope of arrhythmic origin (class IIa) because they are at high risk of recurrent arrhythmic events (up to 10% or more annually for those with aborted cardiac arrest). The majority of BrS patients are asymptomatic when diagnosed and considered to have low risk (around 0.5% annually) and therefore not indicated for ICD. The majority of SCD victims in the BrS, however, had no symptoms prior to the fatal event and therefore were not protected with an ICD. While some ECG markers such as QRS fragmentation, infero-lateral early repolarisation, and abnormal late potentials on signal-averaged ECG are known to be linked to increased arrhythmic risk, they are not sufficiently sensitive or specific. Potential novel ECG-based strategies for risk stratification are discussed based on computerised methods for depolarisation and repolarisation analysis, a composite approach targeting several major components of ventricular arrhythmogenesis, and the collection of large digital ECG databases in genotyped BrS patients and their relatives.

QT dispersion was proposed as an index of the spatial inhomogeneity of ventricular recovery times. The results of studies that found significant correlation between dispersion of ventricular recovery times measured with monophasic action potentials and QT dispersion were interpreted as proof of the direct link between QT dispersion and the dispersion of ventricular recovery times. Later it was shown that QT dispersion is not a direct reflection of the spatial variation of the recovery times and cannot be used for quantification of this variation. The interlead variability of the QT intervals is a result of different projections of the spatial T-wave loop into the various electrocardiographic leads. The reliability of both manual and automatic measurement of QT dispersion is low and is often of the order of the differences of Qt dispersion between different patient groups. The measurement reliability is influenced by intrinsic factors (e.g., amplitude of the T wave) and extrinsic factors (e.g., noise, paper speed of recording, instruments for manual measurements, and type of algorithm and interalgorithmic settings for automatic measurement). There is very little to choose between the different indices of expression of QT dispersion, as well as between the different lead configurations used for its measurement. QT dispersion is not simply a result of measurement error, but a crude measure of abnormalities during the whole course of repolarization. Only grossly prolonged QT dispersion (e.g., > or =100 ms), must be interpreted simply as a sign of the abnormal course of the repolarization, and inferences about the actual dispersion of the ventricular recovery times should not be made. Newer concepts of assessment of the morphology of the T wave are already emerging and will probably be of higher clinical value.

The QT interval has attracted the interest of clinicians and researchers since the very early years of electrocardiography. However, the reasons for this interest have changed significantly over the years. Because of the close correspondence between electrical systole (QT interval) and the mechanical cardiac systole, a fact that was noted by the discoverer of the human electrocardiogram (ECG) Augustus Waller, 1 the QT interval was regarded as a measure of the duration of mechanical systole and an index of cardiac pump function until approximately the 1950s. Prolongation of the QT interval relative to heart rate (the first observations of the relationship between the duration of the mechanical systole and heart rate were published in the middle of the 19th century, several decades before the discovery of the electrocardiogram) was known to occur in various acute and chronic cardiac diseases, electrolyte disturbances, cerebrovascular disorders, during treatment with quinidine, and in rare cases, without identifiable cause in the absence of any of the above conditions (reviewed in 1951 by Bellet 2 ). QT prolongation was considered by many investigators a useful diagnostic sign specifically in acute carditis of rheumatic and other origin. 3,4 The awareness of the link between QT prolongation and the risk of ventricular arrhythmias came much later, with the discovery of the congenital long QT syndrome 5‐7 and torsades de pointes (TdP), 8 but was preceded by clinical ob

We present an excerpt from a 24-hour 12-lead Holter recording acquired in an 85-year-old man investigated for the Brugada syndrome. The rhythm cannot be determined because no P waves can be discerned due to the high level of noise and to merging of the T and P waves. The P waves, however, are clearly visible and the noise is considerably reduced in bipolar precordial leads computed from the standard unipolar precordial leads. The case demonstrates the potential usefulness of various computed leads for rhythm analysis by detecting P waves that are not visible in the standard leads.

In the absence of retrograde (VA) conduction, ventricular pacing does not exert any appreciable effect upon atrial electrical activity. We report three patients (2 with complete AV block and 1 with preserved AV conduction) in which, during EP study, no VA conduction was present and, in spite of that, excessive suppression (for more than 15 secs in the first patient) of sinus (atrial) electrical activity during RV pacing was observed. The sinus node suppression was reproducible in two patients. In all patients the suppression phenomenon was not observed after intravenous administration of atropine, which suggests that it was mediated by enhanced vagal tone.

Food is known to shorten the QT(c) (QT(c)I and QT(c)F) interval and has been proposed as a non-pharmacological method of confirming assay sensitivity in thorough QT (TQT) studies and early phase studies in medicines research. Intake of food leads to a rise in insulin levels together with the release of C-peptide in equimolar amounts. However, it has been reported that euglycaemic hyperinsulinemia can prolong the QT(c) interval, whilst C-peptide has been reported to shorten the QT(c) interval. Currently there is limited information on the effects of insulin and C-peptide on the electrocardiogram (ECG). This study was performed to assess the effect of insulin, glucose and C-peptide on the QT(c) interval under the rigorous conditions of a TQT study.Thirty-two healthy male and female, Caucasian and Japanese subjects were randomized to receive six treatments: (1) placebo, (2) insulin euglycaemic clamp, (3) carbohydrate rich 'continental' breakfast, (4) calorie reduced 'American' FDA breakfast, (5) moxifloxacin without food, and (6) moxifloxacin with food. Measurements of ECG intervals were performed automatically with subsequent adjudication in accordance with the ICH E14 guideline and relevant amendments.No effect was observed on QT(c)F during the insulin euglycaemic clamp period (maximal shortening of QT(c) F by 2.6 ms, not significant). Following ingestion of a carbohydrate rich 'continental' breakfast or a calorie reduced 'American' FDA standard breakfast, a rapid increase in insulin and C-peptide concentrations were observed. Insulin concentrations showed a peak response after the 'continental' breakfast observed at the first measurement time point (0.25 h) followed by a rapid decline. Insulin concentrations observed with the 'American' breakfast were approximately half of those seen with the 'continental' breakfast and showed a similar pattern. C-peptide concentrations showed a peak response at the first measurement time point (0.25 h) with a steady return to baseline at the 6 h time point. The response to the 'continental' breakfast was approximately double that of the 'American' FDA breakfast. A rapid onset of the effect on QT(c) F was observed with the 'continental' breakfast with shortening by5 ms in the time interval from 1 to 4 h. After the 'American' FDA breakfast, a similar but smaller effect was seen.The findings of this study demonstrate that there was no change in QT(c) during the euglycaemic clamp. Given that insulin was raised to physiological concentrations comparable with those seen after a meal, whilst the release of C-peptide was suppressed, insulin appears to have no effect on the QT(c) interval in either direction. The results suggest a relationship exists between the shortening of QT(c) and C-peptide concentrations and indicate that glucose may have a QT(c) prolonging effect, which will require further research.

Aims The authors sought to assess the value of the high right precordial leads (RPL) to detect the Type I Brugada ECG pattern in patients suspected of carrying Brugada syndrome (BrS). Methods Ajmaline testing using 15-lead ECGs was performed in 183 patients suspected of carrying BrS. Standard 12-lead ECG with V1–V3 recorded from the fourth intercostal space and an additional three leads placed over V1–V3 recorded from the third intercostal space were analysed. ECGs were analysed for a Type I ECG pattern in either the standard or high RPLs. Results Of the 183 tests, 31 (17%) were positive, and 152 were negative. In all positive studies, at least one high RPL became positive. In 13/31 (42%) cases, the Type I ECG pattern could be observed only in the high RPLs. Standard or high V3 were never positive before standard or high V1–V2. In seven patients, a Type I pattern was seen in one standard and one high RPL (vertical relationship). Conclusions The high RPLs are more sensitive than the conventional 12-lead ECG alone and initial observations suggest that they remain specific for BrS, while standard and high lead V3 offer redundant data. A vertical relationship of type 1 patterns may have a similar diagnostic value to that of a horizontal pair.

Background: Previous studies have shown conflicting results about the value of heart rate turbulence (HRT) for risk stratification of patients (pts) with chronic heart failure (CHF). We prospectively evaluated the relation between HRT and progression toward end‐stage heart failure or all‐cause mortality in patients with CHF. Methods: HRT was assessed from 24‐hour Holter recordings in 110 pts with CHF (54 in NYHA class II, 56 in class III–IV; left ventricular ejection fraction (LVEF) 30%± 10%) on optimal pharmacotherapy and quantified as turbulence onset (TO,%), turbulence slope (TS, ms/RR interval), and turbulence timing (beginning of RR sequence for calculation of TS, TT). TO ≥ 0%, TS ≤ 2.5 ms/RR, and TT >10 were considered abnormal. End point was development of end‐stage CHF requiring heart transplantation (OHT) or all‐cause mortality. Results: During a follow‐up of 5.8 ± 1.3 years, 24 pts died and 10 required OHT. TO, TS, TT, and both (TO and TS) were abnormal in 35%, 50%, 30%, and 25% of all patients, respectively. Patients with at least one relatively preserved HRT parameter (TO, TS, or TT) (n = 98) had 5‐year event‐free rate of 83% compared to 33% of those in whom all three parameters were abnormal (n = 12). In multivariate Cox regression analysis, the most powerful predictor of end point events was heart rate variability (SDNN < 70 ms, hazard ratio (HR) 9.41, P < 0.001), followed by LVEF ≤ 35% (HR 6.23), TT ≥ 10 (HR 3.14), and TO ≥ 0 (HR 2.54, P < 0.05). Conclusion: In patients with CHF on optimal pharmacotherapy, HRT can help to predict those at risk for progression toward OHT or death of all causes. Ann Noninvasive Electrocardiol 2010;15(3):230–237

Background: Although cases of Brugada-type electrocardiographic (ECG) pattern in peripheral (limb) leads have been reported (“atypical” Brugada syndrome [BS]), their incidence in patients investigated for BS is unknown. Methods: We retrospectively analyzed an ECG database collected during ajmaline test in 143 patients (89 men) with suspected BS. In 42 patients, 12-lead ECGs were recorded, whereas in 101 patients, leads V1–V3 from the third intercostal space were also recorded. The presence of types 1, 2, and 3 Brugada pattern in each limb and precordial lead was noted and the PR, QRS, and QTc intervals were calculated. Results: There were 114 (79.7%) negative and 29 (20.3%) positive tests. Type 1 pattern developed in ≥1 limb lead in six patients (4.2%) (3/29 with positive tests, 10.3%); all of them were male, symptomatic, and/or with family history of BS or sudden cardiac death. Their pre- and posttest QRS were significantly longer compared with the rest with positive (n = 26) or negative (n = 111) test (pretest: 129 ± 31 ms vs 101 ± 11 ms and 97 ± 12 ms, P < 0.001; posttest: 175 ± 44 ms vs 134 ± 14 ms and 131 ± 19 ms, P < 0.001). The posttest QTc was longer in patients with peripheral changes compared with the rest (507 ± 47 ms vs 453 ± 22 ms and 447 ± 24 ms, P < 0.001). The pretest QTc and pre- and posttest heart rate and PR intervals were not significantly different between the three groups. Conclusions: Type 1 Brugada pattern in the peripheral leads was observed in 4.2% of patients during ajmaline test (10.3% of positive tests) and was associated with longer QRS and greater QTc prolongation compared with the rest of the patients.

OBJECTIVES: Mental stress can significantly affect ventricular repolarization, which could potentially trigger arrhythmias. We compared the effect of mental stress on repolarization indexed by the amplitude and area of the T wave in patients with coronary artery disease (CAD) and healthy subjects. METHODS: Fourteen healthy controls (11 M, mean age 42 years) and 14 patients with stable CAD (12 M, mean age 64) underwent a mental stress protocol consisting of mental arithmetic followed by a speech (5 minutes each), which was performed on two occasions following either nitroglycerine (NTG) or placebo. Multiple 12-lead electrocardiograms were acquired and repolarization was analyzed using automatically measured T wave amplitude (T(amp)) and area (T(area)). RESULTS: When preceded by placebo the overall effect of mental stress, whether induced by arithmetic or speech, was significantly different in CAD patients compared with controls, with a decrease in T(amp) and T(area) in controls and an increase in patients; e.g., change in T(amp) during arithmetic -20 +/- 3 microV in controls versus 4 +/- 2 microV in patients, p < .001, and during speech -9 +/- 3 microV in controls versus 7 +/- 1 microV in patients, p < .001. Following NTG, the effect of stress on repolarization was similar in the 2 groups, with a reversed effect, i.e., decrease instead of increase in T(amp) and T(area) in CAD patients. CONCLUSIONS: The effect of mental stress on ventricular repolarization is significantly different in CAD patients compared with healthy controls. These differences are considerably reduced by NTG.

We tested the hypothesis that ventricular repolarization of the first sinus beat following a ventricular premature beat (VPB) can be modulated in the absence of clearly discernible T‐wave changes. We applied principal component analysis (PCA) to assess QRS and T‐wave complexity of sinus beats preceding and following VPBs in multiple 10‐second resting 12‐lead electrocardiograms of two subjects with frequent VPBs and no apparent heart disease. In both subjects, T‐wave complexity of the first post‐VPB beat was significantly increased compared to the beats preceding the VPB.

Background We investigated the predictive value of the spatial QRS-T angle (QRSTA) circadian variation in myocardial infarction (MI) patients. Methods Analyzing 24-hour recordings (SEER MC, GE Marquette) from 151 MI patients (age 63 ± 12.7), the QRSTA was computed in derived XYZ leads. QRS-T angle values were compared between daytime and night time. The end point was cardiac death or life-threatening ventricular arrhythmia in 1 year. Results Overall, QRSTA was slightly higher during the day vs. the night (91° vs. 87°, P = .005). However, 33.8% of the patients showed an inverse diurnal QRSTA variation (higher values at night), which was correlated to the outcome ( P = .001, odds ratio 6.7). In multivariate analysis, after entering all factors exhibiting univariate trend towards significance, inverse QRSTA circadian pattern remained significant ( P = .036). Conclusion Inverse QRSTA circadian pattern was found to be associated with adverse outcome (22.4%) in MI patients, whereas a normal pattern was associated (96%) with a favorable outcome.