Greg Mellor

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.

The prevalence and significance of a short QT interval in 18 825 low-risk individuals including athletes

Objectives The short QT syndrome is a cardiac channelopathy characterised by accelerated repolarisation which manifests as a short QT interval on the ECG. The definition of a short QT interval is debated, ranging from <390 to ≤320 ms, and its clinical significance in healthy young individuals is unknown. We assessed the prevalence and medium-term significance of an isolated short QT interval in a diverse young British population. Methods Between 2005 and 2013, 18 825 apparently healthy people aged 14–35 years underwent cardiovascular evaluation with history, physical examination and ECG. QT intervals were measured by cardiologists using 4 recommended guidelines (Seattle 2013, Heart Rhythm Society 2013, European Society of Cardiology 2010 and American Heart Association 2009). Results The prevalence of a short QT interval was 0.1% (26 patients, ≤320 ms), 0.2% (44 patients, ≤330 ms), 7.9% (1478 patients, <380 ms), 15.8% (2973 patients, <390 ms). Male gender and Afro-Caribbean ethnicity had the strongest association with short QT intervals. Athletes had shorter QT intervals than non-athletes but athletic status did not predict short QT intervals. Individuals with short QT intervals ≤320 ms did not report syncope or a sinister family history, and during a follow-up period of 5.3±1.2 years, there were no deaths in this group. Conclusions The prevalence of a short QT interval depends on the recommended cut-off value. Even at values ≤320 ms, there was an excellent medium-term prognosis among 14 people followed. We conclude that a definition of ≤320 ms is realistic to prevent overdiagnosis and excessive investigations.

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.

Inter-Rater Reliability and Downstream Financial Implications of Electrocardiography Screening in Young Athletes

Background— Preparticipation screening for cardiovascular disease in young athletes with electrocardiography is endorsed by the European Society of Cardiology and several major sporting organizations. One of the concerns of the ECG as a screening test in young athletes relates to the potential for variation in interpretation. We investigated the degree of variation in ECG interpretation in athletes and its financial impact among cardiologists of differing experience. Methods and Results— Eight cardiologists (4 with experience in screening athletes) each reported 400 ECGs of consecutively screened young athletes according to the 2010 European Society of Cardiology recommendations, Seattle criteria, and refined criteria. Cohen &kgr; coefficient was used to calculate interobserver reliability. Cardiologists proposed secondary investigations after ECG interpretation, the costs of which were based on the UK National Health Service tariffs. Inexperienced cardiologists were more likely to classify an ECG as abnormal compared with experienced cardiologists (odds ratio, 1.44; 95% confidence interval, 1.03–2.02). Modification of ECG interpretation criteria improved interobserver reliability for categorizing an ECG as abnormal from poor (2010 European Society of Cardiology recommendations; &kgr;=0.15) to moderate (refined criteria; &kgr;=0.41) among inexperienced cardiologists; however, interobserver reliability was moderate for all 3 criteria among experienced cardiologists (&kgr;=0.40–0.53). Inexperienced cardiologists were more likely to refer athletes for further evaluation compared with experienced cardiologists (odds ratio, 4.74; 95% confidence interval, 3.50–6.43) with poorer interobserver reliability (&kgr;=0.22 versus &kgr;=0.47). Interobserver reliability for secondary investigations after ECG interpretation ranged from poor to fair among inexperienced cardiologists (&kgr;=0.15–0.30) and fair to moderate among experienced cardiologists (&kgr;=0.21–0.46). The cost of cardiovascular evaluation per athlete was

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

175 (95% confidence interval,

Genetic Testing in the Evaluation of Unexplained Cardiac ArrestCLINICAL PERSPECTIVE: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry)

142–

Quinidine effective for the management of ventricular and atrial arrhythmias associated with Brugada syndrome

228) and

Reply: How Often Does Athlete Sudden Cardiac Death Occur Outside the Context of Exertion?

101 (95% confidence interval,

Etiology of Sudden Death in Sports: Insights From a United Kingdom Regional Registry

83–

Genetic Testing in the Evaluation of Unexplained Cardiac Arrest: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry)

131) for inexperienced and experienced cardiologists, respectively. Conclusions— Interpretation of the ECG in athletes and the resultant cascade of investigations are highly physician dependent even in experienced hands with important downstream financial implications, emphasizing the need for formal training and standardized diagnostic pathways.