Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The Robert Lancaster Memorial Fund sponsored by McColl’s Research Group British Heart Foundation. Background Clinical, electrocardiographic, and genomic factors associated with the development of the drug induced type 1 Brugada pattern (DI-T1BP), in response to sodium channel blocker provocation (SCBP) have been investigated. However, these prior analyses have mostly been concerned with the prediction of the DI-T1BP rather than the strength or validity of the diagnosis of Brugada syndrome (BrS). We sought to analyse and compare the ECG response to SCBP with Ajmaline in a cohort of healthy subjects (Healthy Controls) and clinical patients with a DI-T1BP and a Shanghai Score (ShS) >3.5 (Definite-BrS group). Methods From an existing clinical cohort of consecutive patients investigated at our centre between 2010 - 2022, we identified those with a DI-T1BP and a ShS >3.5. Respondents to a national advertisement, completed an online medical questionnaire. Those fulfilling the inclusion criteria were invited to undergo further evaluation with eligible subjects being recruited to the healthy control group. All subjects received a diagnostic AP (1mg/kg max. 100mg over 5 minutes). A continuous ECG was recorded in the standard and high right precordial lead (HRPL) position. Automated analysis of conventional and novel ECG measurements were made at baseline and at peak drug effect, which was defined as the point of maximum QRS duration (excluding precordial leads). Results One hundred healthy controls and 166 patients with definite BrS were recruited, Table 1.0. This included 51 (31%) BrS probands. In the definite BrS group, the mean pre-ajmaline ShS was 2.1 (± 0.80) and mean final ShS was 4.3 (± 0.75). In comparison to healthy controls, the time to peak drug effect was significantly earlier in definite BrS patients, 05:18 (±02:05) vs. 05:59 (± 01:20). Whilst the increase in global QRS duration was greater in the definite BrS group, ∆37.78ms (± 18.16ms) vs. ∆25.66ms (±11.98) P<0.01, the increase in PR interval was greater in the healthy control group, ∆43.36ms (±17.27ms) vs. ∆20.77ms (±31.64ms), P<0.01. Compared to the healthy controls, the definite BrS group experienced a pronounced increase in anterior ST-J point amplitude ∆27.58µV (±27.70) vs. 115.37µV(±106.41), P<0.01, respectively. In contrast, whilst there was a reduction in inferior and lateral ST-J point amplitude in the definite BrS group, healthy controls demonstrated an increase in amplitude in these regions, Table 2.0. Mean QRS area was significantly greater at peak drug effect in the definite BrS group, ∆0.14V/s (±0.31) vs. ∆-0.20 (±0.18), P <0.01, whilst T wave area showed a reduction. Conclusion In addition to the DI-T1BP patients with definite BrS experience a number of ECG characteristics that might allow for a quantitative refinement of the diagnosis.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation The Robert Lancaster Memorial Fund sponsored by McColl’s Research Group Background The electrocardiographic (ECG) response to diagnostic ajmaline provocation (AP) testing has been studied extensively in clinical cohorts. However, the healthy ECG response has not been described. We undertook a trial examining ECG changes in response to AP in a cohort of systematically recruited asymptomatic Caucasian healthy subjects with no family history of sudden death and normal baseline ECG and echocardiogram. Methods Applicants responded to a national recruitment advertisement and completed an online medical questionnaire. Those fulfilling inclusion criteria were invited to undergo further evaluation with eligible subjects undergoing a diagnostic ajmaline challenge (1mg/kg, max. 100mg over 5 minutes). A continuous ECG was recorded in the standard and high right precordial lead (HRPL) position. Automated analysis of conventional and novel ECG measurements were made at baseline and at peak drug effect, which was defined as the point of maximum QRS duration (excluding precordial leads). Results One hundred healthy Caucasian subjects underwent AP. The mean age was 26.84 years (SD ± 8.01 years) and 52% were male. A drug induced type 1 Brugada pattern (DI-T1BP) was observed in 3/100 (3%) of the cohort. We performed a paired comparison of ECG measures at baseline versus peak drug effect (Table 1). AP had a similar effect on global QRS duration and global PR interval, with both increasing by 28%, mean ∆ 25.66ms and mean ∆ 43.36ms respectively. Changes in S wave parameters in lead II were pronounced, with a 97% increase in S wave duration and a 101% increase in S wave negative amplitude. ST-J point elevation in the anterior, inferior, and lateral regions was comparable, with a 57%, 51% and 57% increase in ST-J amplitude respectively. AP had a greater effect on cardiac conduction in females compared to males (Table 2). In contrast, changes in STJ point amplitude and combined and segmented QRST segment area were greater in males. Conclusion The healthy ECG response to AP elicits a pronounced effect on cardiac conduction, more so in females compared to males, whilst changes in STJ point amplitude and QRST area were greater in male subjects. The DI-T1BP is part of the healthy response to AP.

Patients with suspected Brugada syndrome often undergo a procainamide challenge to stratify their risk for sudden death and arrhythmic events. Patients that develop a Type 1 Brugada pattern during procainamide infusion are at greater risk for cardiac arrest. The signal-averaged ECG (SAECG) can detect late potentials in Brugada syndrome, which may have prognostic significance. We used historical and clinical features, and the SAECG to predict the yield of the procainamide and ajmaline tests in patients with suspected Brugada syndrome. 251 patients were enrolled across Canada with a procainamide challenge and standard, high precordial, and signal-averaged ECGs. A second cohort of 97 patients were enrolled in the United Kingdom, undergoing ajmaline challenge. We evaluated 6 variables including: sex, syncope, palpitations, previous cardiac arrest, baseline ST-elevation (STE; Type 2 or 3 Brugada pattern), and abnormal SAECG. We derived and validated a parsimonious model to predict the outcome of the sodium channel blocker challenge. The average age was 43±15 years (61% male). 100 patients (40%) had a cardiac arrest, 54 (22%) had syncope, and 24 (10%) had palpitations prior to assessment. 83 patients (33%) had baseline STE and 20 patients (8%) had a positive procainamide challenge. Univariate and multivariate analysis identified baseline STE (OR 50.7) and SAECG (OR 1.84 per parameter) to be associated with a positive procainamide challenge (see Table). A simple 2-factor, 6-point model derived using baseline STE (3 points) and SAECG (1 point per parameter) was strongly predictive of the procainamide challenge (AUC 0.876). This model was validated in a second cohort, and found to be moderately predictive of the ajmaline challenge (AUC 0.730). Patients that scored 0 were unlikely to have a positive test (100% sensitivity), and patients that scored 6 were very likely to have a positive test (93% specificity). In this combined cohort of 348 patients, we derived and validated a simple 2-factor, 6-point score that can be effectively used to triage the role of the procainamide and ajmaline challenge in patients with suspected Brugada syndrome. Our findings also highlight the utility and incremental value of the SAECG in stratifying patients with suspected Brugada syndrome, prior to a sodium channel blocker test. We identified two populations where the sodium channel blocker test could be avoided to prevent adverse events and ensure appropriate use of resources.

Introduction A gold standard test for arrhythmogenic right ventricular cardiomyopathy (ARVC) does not exist and diagnosis relies on meeting Task Force criteria. Sudden death remains the first clinical presentation in up to 23% of subjects. In ischaemic heart disease prolongation of the ventricular ectopic QS interval (VEQSI) has been shown to correlate with presence and severity of myocardial disease. We evaluated the significance of VEQSI in patients with ARVC. Methods We selected 3 cohorts for 12 lead 24-h Holter monitoring: 51 normal controls (41.7±14.8 years; 55% male); 27 patients with definite ARVC by Task Force criteria (46.4±13.1 years; 70% male); 10 patients with borderline ARVC and a confirmed pathogenic mutation and/or definitely affected first degree relative (34.6±13.0 years; 50% male). All ventricular ectopics (VE) were reviewed and VEQSI was measured for each VE morphology. The longest VE duration was recorded as VEQSI max. Results VEQSI max was significantly longer in definite ARVC compared with borderline ARVC and normal controls (208.8±18.6 ms, 183.7±12.9 ms and 155.0±14.4 ms respectively; p<0.001). VEQSI max was also significantly longer in borderline ARVC compared with normal controls (p=0.002). When the upper normal limit for VEQSI max was defined as 170 ms there was 97% sensitivity and 93% specificity for diagnosis of ARVC, including 9/10 correct diagnoses in the borderline ARVC group. Conclusion Maximal VEQSI duration is significantly longer in definite ARVC compared with normal controls, and intermediate in ARVC patients with early disease. VEQSI max >170 ms has high sensitivity and specificity for the diagnosis of ARVC and may be particularly useful in borderline disease.

068 Figure 1 069 SYSTEMATIC REVIEW OF 1142 ADMISSIONS WITH ACUTE HEART FAILURE REVEALS HIGH FREQUENCY OF TRANSTHYRETIN V122I CARDIAC AMYLOIDOSIS IN AFROCARIBBEAN PATIENTS doi:10.1136/heartjnl-2012-301877b.69 J Dungu,* M S O’Donnell, P N Hawkins, L J Anderson. St George’s University of London, London, UK; National Amyloidosis Centre, UK Background The genetic mutation encoding transthyretin (TTR) isoleucine 122 (V122I) is present in 3.9% of African-Americans and associated with cardiac TTR amyloidosis, but penetrance is unknown. Little is known about the frequency or clinical phenotype of TTR V122I amyloidosis in the British Afro-Caribbean population. Methods We reviewed the primary diagnoses of 1142 patients admitted with heart failure between September 2005 and February 2011. The diagnosis was supported by echocardiography, cardiac MRI (in patients without contraindications) and genetic testing; endomyocardial biopsies were performed in 68 patients (6%) in whom amyloidosis was suspected or uncertainty about diagnosis remained. Survival analysis was performed to August 2011. Results The median age was 72 years (range 18e98) with male (66.7%) and Caucasian (71.0%) predominance. Ischaemic cardiomyopathy (ICM) was the primary diagnosis in 428 patients (37%). There were 170 Afro-Caribbean patients (14.9%) among whom ICM was less common (22 patients (13%), p<0.01). Seventeen AfroCaribbean patients (10%) were confirmed to have cardiac ATTR V122I amyloidosis. Survival of Afro-Caribbean patients with ICM and ATTR V122I amyloidosis was similar (45 vs 36 months, p1⁄40.54), but overall survival (n1⁄41142) was significantly inferior in cardiac amyloidosis compared to non-amyloid cardiomyopathy (34 vs 59 months, p<0.01). Conclusion ATTRV122I amyloidosis is an important cause of heart failure in the British Afro-Caribbean population, but it is commonly misdiagnosed as hypertensive cardiomyopathy. Diagnosis requires specialist multidisciplinary investigation including CMR, genetic testing and histology, enabling appropriate management in an era when novel treatments for amyloidosis are entering the clinic. Abstract 069 Figure 1 KaplaneMeier curves for all patients (n1⁄41142) demonstrating significantly inferior survival in cardiac amyloidosis compared to non-amyloid cardiomyopathy (p<0.01). KaplaneMeier curves in Afro-Caribbean patients (N1⁄4170) demonstrating no significant difference in survival between ischaemic cardiomyopathy and ATTR V122I (p1⁄40.54).069 Figure 1 KaplaneMeier curves for all patients (n1⁄41142) demonstrating significantly inferior survival in cardiac amyloidosis compared to non-amyloid cardiomyopathy (p<0.01). KaplaneMeier curves in Afro-Caribbean patients (N1⁄4170) demonstrating no significant difference in survival between ischaemic cardiomyopathy and ATTR V122I (p1⁄40.54). Heart May 2012 Vol 98 Suppl 1 A39 BCS Abstracts 2012 group.bmj.com on September 7, 2017 Published by http://heart.bmj.com/ Downloaded from

Aims: To assess the value of the high precordial leads, (V1 to V3 from the 3rd intercostal space, V1h to V3h) during ajmaline testing in the diagnosis of Brugada syndrome (BS).

Patients with specific neurological, psychiatric or cardiovascular conditions are at enhanced risk of cardiac arrhythmia and sudden death. The neurogenic mechanisms are poorly understood. However, in many cases, stress may precipitate cardiac arrhythmia and sudden death in vulnerable patients, presumably via centrally driven autonomic nervous system responses. From a cardiological perspective, the likelihood of arrhythmia is strongly associated with abnormalities in electrical repolarization (recovery) of the heart muscle after each contraction. Inhomogeneous and asymmetric repolarization, reflected in ECG T-wave abnormalities, is associated with a greatly increased risk of arrhythmia, i.e. a proarrhythmic state. We therefore undertook a study to identify the brain mechanisms by which stress can induce cardiac arrhythmia through efferent autonomic drive. We recruited a typical group of 10 out-patients attending a cardiological clinic. We simultaneously measured brain activity, using H2(15)O PET, and the proarrhythmic state of the heart, using ECG, during mental and physical stress challenges and corresponding control conditions. Proarrhythmic changes in the heart were quantified from two ECG-derived measures of repolarization inhomogeneity and were related to changes in magnitude and lateralization of regional brain activity reflected in regional cerebral blood flow. Across the patient group, we observed a robust positive relationship between right-lateralized asymmetry in midbrain activity and proarrhythmic abnormalities of cardiac repolarization (apparent in two independent ECG measures) during stress. This association between stress-induced lateralization of midbrain activity and enhanced arrhythmic vulnerability provides empirical support for a putative mechanism for stress-induced sudden death, wherein lateralization of central autonomic drive during stress results in imbalanced activity in right and left cardiac sympathetic nerves. A right-left asymmetry in sympathetic drive across the surface of the heart disrupts the electrophysiological homogeneity of ventricular repolarization, predisposing to arrhythmia. Our findings highlight a proximal brain basis for stress-induced cardiac arrhythmic vulnerability.

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)

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).