The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy.

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.

The ventricular ectopic QRS interval (VEQSI): Diagnosis of arrhythmogenic right ventricular cardiomyopathy in patients with incomplete disease expression.

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.

Novel electrocardiographic criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy.

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. 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. 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.

QRS-ST-T triangulation with repolarization shortening as a precursor of sustained ventricular tachycardia during acute myocardial ischemia.

We present segments from a 24-hour 12-lead digital Holter recording in a 48-year-old man demonstrating transient ST elevations in the inferior leads that triggered sustained ventricular tachycardia/ventricular fibrillation (VT/VF) requiring cardioversion. The onset of VT was preceded by a gradual increase in the ST with marked QRS broadening that lacked distinction between the end of the QRS and the beginning of the ST (QRS-ST-T "triangulation"), and shortening of the QT interval not caused by an increased heart rate. This is a relatively rare documentation of the mechanisms immediately triggering sustained ventricular arrhythmias during acute myocardial ischemia obtained with 12-lead ECG.

Electrocardiographic methods for diagnosis and risk stratification in the Brugada syndrome.

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.

The Syndrome of Inter-atrial Conduction Block.

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.

Computed bipolar precordial leads for improved P wave detection.

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.

Clinical utility of computed electrocardiographic leads.

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.

The Brugada Syndrome - Diagnosis, Clinical Implications and Risk Stratification.

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.

Insulin at normal physiological levels does not prolong QT(c) interval in thorough QT studies performed in healthy volunteers.

AIMS: 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. 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 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 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 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.

Characterization of early repolarization during ajmaline provocation and exercise tolerance testing.

BACKGROUND: 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. OBJECTIVE: To examine the response to ajmaline provocation and exercise in potentially high-risk subjects with ER and without a definitive cardiac diagnosis. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prevalence of the type 1 Brugada electrocardiogram in Caucasian patients with suspected coronary spasm.

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.

Utility of high and standard right precordial leads during ajmaline testing for the diagnosis of Brugada syndrome.

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.

Heart rate turbulence for prediction of heart transplantation and mortality in chronic heart failure.

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 > or = 0%, TS < or = 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 < or = 35% (HR 6.23), TT > or = 10 (HR 3.14), and TO > or = 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.

Diagnostic utility of bipolar precordial leads during ajmaline testing for suspected Brugada syndrome.

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.