Hariharan Raju

Sudden Cardiac Death With Autopsy Findings of Uncertain Significance Potential for Erroneous Interpretation

Background—The sudden death of young individuals is commonly attributed to inherited cardiac disorders, and familial evaluation is advocated. The identification of pathognomonic histopathologic findings, or the absence of cardiac pathology (sudden arrhythmic death syndrome [SADS]) at postmortem, directs familial evaluation targeting structural disorders or primary arrhythmogenic syndromes, respectively. In a proportion of autopsies, structural abnormalities of uncertain significance are reported. We explored the hypothesis that such sudden cardiac deaths represent SADS. Methods and Results—Families (n=340) of index cases of sudden cardiac deaths who underwent postmortem evaluation were evaluated in specialist cardiogenetics clinics. Families in whom the deceased exhibited structural abnormalities of uncertain significance (n=41), such as ventricular hypertrophy, myocardial fibrosis, and minor coronary artery disease, were included in the study. Results were compared with 163 families with normal postmortem (SADS). Relatives underwent comprehensive cardiac evaluation. Twenty-one families (51%) with autopsy findings of uncertain significance received a diagnosis based on the identification of an inherited cardiac condition phenotype in ≥1 relatives: 14 Brugada syndrome; 4 long-QT syndrome; 1 catecholaminergic polymorphic ventricular tachycardia; and 2 cardiomyopathy. A similar proportion of families (47.2%) received a diagnosis in the SADS cohort (P=0.727). An arrhythmogenic syndrome was the predominant diagnosis in both cohorts (46% versus 45%; P=0.863). Conclusions—Familial evaluation after sudden cardiac deaths with autopsy findings of uncertain significance identified a similar proportion of primary arrhythmogenic syndromes to a contemporary series of SADS. Our study highlights the need for accurate interpretation of autopsy findings to avoid erroneous diagnoses, with potentially devastating implications.

Should axis deviation or atrial enlargement be categorised as abnormal in young athletes? The athlete's electrocardiogram: time for re-appraisal of markers of pathology

AIMS The 2010 European Society of Cardiology (ESC) guidelines for electrocardiogram (ECG) interpretation in athletes are associated with a relatively high false positive rate and warrant modification to improve the specificity without compromising sensitivity. The aim of this study was to investigate whether non-specific anomalies such as axis deviation and atrial enlargement in isolation require further assessment in highly trained young athletes. METHOD AND RESULTS Between 2003 and 2011, 2533 athletes aged 14-35 years were investigated with 12-lead ECG and echocardiography. Electrocardiograms were analysed for non-training-related (Group 2) changes according to the 2010 ESC guidelines. Results were compared with 9997 asymptomatic controls. Of the 2533 athletes, 329 (13%) showed Group 2 ECG changes. Isolated axis deviation and isolated atrial enlargement comprised 42.6% of all Group 2 changes. Athletes revealed a slightly higher prevalence of these anomalies compared with controls (5.5 vs. 4.4%; P = 0.023). Echocardiographic evaluation of athletes and controls with isolated axis deviation or atrial enlargement (n = 579) failed to identify any major structural or functional abnormalities. Exclusion of axis deviation or atrial enlargement reduced the false positive rate from 13 to 7.5% and improved specificity from 90 to 94% with a minimal reduction in sensitivity (91-89.5%). CONCLUSION Isolated axis deviation and atrial enlargement comprise a high burden of Group 2 changes in athletes and do not predict underlying structural cardiac disease. Exclusion of these anomalies from current ESC guidelines would improve specificity and cost-effectiveness of pre-participation screening with ECG.

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.

Clinical significance of electrocardiographic right ventricular hypertrophy in athletes: comparison with arrhythmogenic right ventricular cardiomyopathy and pulmonary hypertension

AIMS Pre-participation cardiovascular screening of young athletes may prevent sports-related sudden cardiac deaths. Recognition of physiological electrocardiography (ECG) changes in healthy athletes has improved the specificity of screening while maintaining sensitivity for disease. The study objective was to determine the clinical significance of electrocardiographic right ventricular hypertrophy (RVH) in athletes. METHODS AND RESULTS Between 2010 and 2012, 868 subjects aged 14-35 years (68.8% male) were assessed using ECG and echocardiography (athletes; n = 627, sedentary controls; n = 241). Results were compared against patients with established right ventricular (RV) pathology (arrhythmogenic right ventricular cardiomyopathy, n = 68; pulmonary hypertension, n = 30). Sokolow-Lyon RVH (R[V1]+S[V5orV6] > 1.05 mV) was more prevalent in athletes than controls (11.8 vs. 6.2%, P = 0.017), although RV wall thickness (RVWT) was similar (4.0 ± 1.0 vs. 3.9 ± 0.9 mm, P = 0.18). Athletes exhibiting electrocardiographic RVH were predominantly male (95.9%), and demonstrated similar RV dimensions and function to athletes with normal electrocardiograms (RVWT; 4.0 ± 1.1 vs. 4.0 ± 0.9 mm, P = 0.95, RV basal dimension; 42.7 ± 5.2 vs. 42.1 ± 5.9 mm, P = 0.43, RV fractional area change; 40.6 ± 7.6 vs. 42.2 ± 8.1%, P = 0.14). Sensitivity and specificity of Sokolow-Lyon RVH for echocardiographic RVH (>5 mm) were 14.3 and 88.2%, respectively. Further evaluation including cardiac magnetic resonance imaging did not diagnose right ventricular pathology in any athlete. None of the cardiomyopathic or pulmonary hypertensive patients exhibited voltage RVH without additional ECG abnormalities. CONCLUSION Electrocardiographic voltage criteria for RVH are frequently fulfilled in healthy athletes without underlying RV pathology, and should not prompt further evaluation if observed in isolation. Recognition of this phenomenon should reduce the burden of investigations after pre-participation ECG screening without compromising sensitivity for disease.

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

Background Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. Objectives This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. Methods We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. Results A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. Conclusions Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

Clinical Characteristics and Circumstances of Death in the Sudden Arrhythmic Death Syndrome

Background—Sudden cardiac death (SCD) is a devastating event in the young. Referral to a specialist cardiac pathologist is recommended. Age, sex, and circumstances of death may reflect underlying diagnoses. We aim to describe the demographics of victims and circumstances surrounding sudden cardiac death with a normal heart (ie, sudden arrhythmic death syndrome). Methods and Results—There were 2156 cases of sudden cardiac death from across the United Kingdom referred to a tertiary cardiac pathology service from 1994 to 2010. We analyzed 967 consecutive cases (61% male; median age 29 years) with a normal heart at postmortem. Information from referring coroners’ reports was used to ascertain clinical information. Familial evaluation was performed in 5% of cases. Information from these cases was used to determine the likely accuracy of coronial reports. Deaths during sleep or at rest were more common than deaths during exercise or with emotional stress: 82% versus 16%. Death with exercise/stress was more common in males (relative risk, 2.33; 95% confidence interval, 1.56–3.47; P<0.001) and those under 18 years of age: males, relative risk, 2.41 (95% confidence interval, 1.69–3.13; P<0.001) and females, relative risk, 2.91 (95% confidence interval, 1.80–4.01; P<0.001)). Prior syncope (4.1%), documented arrhythmia (3.4%), and family history of sudden death (4.2%) were uncommon. Epilepsy had been diagnosed in 6.6%. Conclusions—Death caused by sudden arrhythmic death syndrome is more common at rest or during sleep. Death with exercise/stress is more common in males and those aged below 18 years. Up to 90% of SADS victims have no preceding symptoms or recognized risk factors for sudden death. Epilepsy may be considered a risk factor for SADS.

Unexplained sudden death, focussing on genetics and family phenotyping.

Purpose of review Unexplained sudden death and the sudden arrhythmic death syndrome (SADS) affect a small but significant proportion of young and apparently healthy individuals. This review revisits the causes underlying such deaths and the investigational strategies that identify surviving family who may be at risk. Recent findings Recent epidemiological data is available from case series or government records. The yield from familial cardiological evaluation for inherited conditions has been supported by additional small series. The greatest advance has come with molecular autopsy studies, which have utilized various methodologies and candidate genes to investigate SADS cases and their families. Summary The latest research replicates and extends the existing knowledge regarding epidemiology and familial evaluation of SADS, whilst genetic studies support a role for the molecular autopsy.

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.

The Prevalence and Significance of the Early Repolarization Pattern in Sudden Arrhythmic Death Syndrome Families

Background—The early repolarization (ER) pattern is associated with sudden death and has been shown to be heritable. Its significance when identified in families affected by sudden arrhythmic death syndrome (SADS) remains unclear. Methods and Results—We analyzed 12-lead ECGs of 401 first-degree relatives of individuals who had died from SADS. The prevalence of ER patterns was compared with family-clustered controls. ER was more common in SADS family members than in controls (21% versus 8%; odds ratio: 5.14; 95% confidence interval, 3.37–7.84) independent of the presence of a familial cardiac diagnosis. Both ascending and horizontal ER patterns were more common. In addition, ER was investigated for associations with findings from ajmaline provocation (n=332), exercise ECG (n=304), and signal-averaged ECG (n=118) when performed. ER was associated with a trend toward late depolarization, in general was suppressed with exercise and was unaffected by ajmaline. Inferior and horizontal patterns were, however, more likely to persist during exercise. Augmentation of ER with ajmaline was rare. Conclusions—The ER pattern is more common in SADS family members than controls adjusted in particular for relatedness. The increased prevalence is irrespective of ER subtype and the presence of other inherited arrhythmia syndromes. ER may therefore represent an underlying heritable arrhythmia syndrome or risk factor for sudden death in the context of other cardiac pathology. The differing response of ER subtypes to exercise and ajmaline provocation suggests underlying mechanisms of both abnormal repolarization and depolarization.

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.