Elijah R. Behr

HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013.

Developed in partnership with the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology, and the Asia Pacific Heart Rhythm Society (APHRS); and in collaboration with the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the Pediatric and Congenital Electrophysiology Society (PACES) and the Association for European Pediatric and Congenital Cardiology (AEPC).

Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families

AIMS At least 4% of sudden deaths are unexplained at autopsy [sudden arrhythmic death syndrome (SADS)] and a quarter may be due to inherited cardiac disease. We hypothesized that comprehensive clinical investigation of SADS families would identify more susceptible individuals and causes of death. METHODS AND RESULTS Fifty seven consecutively referred families with SADS death underwent evaluation including resting 12 lead, 24 h and exercise ECG and 2D echocardiography. Other investigations included signal averaged ECG, ajmaline testing, cardiac magnetic resonance imaging, and mutation analysis. First-degree relatives [184/262 (70%)] underwent evaluation, 13 (7%) reporting unexplained syncope. Seventeen (30%) families had a history of additional unexplained premature sudden death(s). Thirty families (53%) were diagnosed with inheritable heart disease: 13 definite long QT syndrome (LQTS), three possible/probable LQTS, five Brugada syndrome, five arrhythmogenic right ventricular cardiomyopathy (ARVC), and four other cardiomyopathies. One SCN5A and four KCNH2 mutations (38%) were identified in 13 definite LQTS families, one SCN5A mutation (20%) in five Brugada syndrome families and one (25%) PKP2 (plakophyllin2) mutation in four ARVC families. CONCLUSION Over half of SADS deaths were likely to be due to inherited heart disease; accurate identification is vital for appropriate prophylaxis amongst relatives who should undergo comprehensive cardiological evaluation, guided and confirmed by mutation analysis.

Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.

and Management of Patients with Inherited Primary Arrhythmia Syndromes Silvia G. Priori, MD, PhD, (HRS Chairperson), Arthur A. Wilde, MD, PhD, (EHRA Chairperson), Minoru Horie, MD, PhD, (APHRS Chairperson), Yongkeun Cho, MD, PhD, (APHRS Chairperson), Elijah R. Behr, MA, MBBS, MD, FRCP, Charles Berul, MD, FHRS, CCDS, Nico Blom, MD, PhD*, Josep Brugada, MD, PhD, Chern-En Chiang, MD, PhD, Heikki Huikuri, MD, Prince Kannankeril, MD, Andrew Krahn, MD, FHRS, Antoine Leenhardt, MD, Arthur Moss, MD, Peter J. Schwartz, MD, Wataru Shimizu, MD, PhD, Gordon Tomaselli, MD, FHRS, Cynthia Tracy, MD From the Maugeri Foundation IRCCS, Pavia, Italy, Department of Molecular Medicine, University of Pavia, Pavia, Italy and New York University, New York, New York, Department of Cardiology, Academic Medical Centre, Amsterdam, Netherlands, Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia, Shiga University of Medical Sciences, Otsu, Japan, Kyungpook National University Hospital, Daegu, South Korea, St. Georges University of London, United Kingdom, Children’s National Medical Center, Washington, DC, United States, Academical Medical Center, Amsterdam, Leiden University Medical Center, Leiden, Netherlands, University of Barcelona, Barcelona, Spain, Taipei Veteran’s General Hospital, Taipei, Taiwan, Oulu University Central Hospital, Oulu, Finland, Vanderbilt Children’s Hospital, Nashville, Tennessee, United States, Sauder Family and Heart and Stroke Foundation University of British Columbia, British Columbia, Canada, Bichat University Hospital, Paris, France, University of Rochester Medical Center, Rochester, New York, United States, Department of Molecular Medicine, University of Pavia, Pavia, Italy, Nippon Medical School, Tokyo, Japan, Johns Hopkins University, Baltimore, Maryland, United States, and George Washington University Medical Center, Washington, DC, United States.

Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome

4.1% of sudden cardiac deaths in the 16-64 age-group are unexplained. In this group, cardiac pathological findings are normal and toxicological tests are negative; termed sudden arrhythmic death syndrome (SADS). We searched for evidence of inherited cardiac disease in cases of SADS. Of 147 first-degree relatives of 32 people who died of SADS, 109 (74%) underwent cardiological assessment. Seven (22%) of the 32 families were diagnosed with inherited cardiac disease: four with long QT syndrome; one with non-structural cardiac electrophysiological disease; one with myotonic dystrophy; and one with hypertrophic cardiomyopathy. Families of people who die of SADS should be offered assessment in centres with experience of inherited cardiac disease.

Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Hypertrophic cardiomyopathy: management, risk stratification, and prevention of sudden death

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac muscle disorder disease that affects sarcomeric proteins, resulting in small vessel disease, myocyte and myofibrillar disorganisation, and fibrosis with or without myocardial hypertrophy. These features may result in significant cardiac symptoms and are a potential substrate for arrhythmias. Before the identification of disease causing genes the World Health Organization defined HCM as the presence of left or biventricular hypertrophy in the absence of any cardiac or systemic cause.w1 When these criteria are applied to a western population the estimated prevalence of HCM is approximately 1 in 500.1w2 Morphological evidence of left ventricular hypertrophy, however, may be absent in up to 20% of gene carriers.w3 Adults are often asymptomatic but their estimated mortality rate may nonetheless be as high as 1–2% per annum.2w4 This article will present the natural history of HCM and relate it to the need for medical intervention to alleviate symptoms and prevent sudden death. The expression of disease is age related, occurring during or soon after periods of rapid somatic growth. Detectable cardiovascular abnormalities usually develop during adolescence.w5 For this reason the regular evaluation of the offspring of carriers during puberty and early adulthood is necessary for diagnosis and risk stratification. HCM has been described in infants and young children but data are limited. Children diagnosed before 14 years of age have a worse prognosis once they reach adolescence and early adulthood with a 2–4% annual incidence of sudden death.3 The development of clinical features of HCM in the elderly is associated with myosin binding protein C (MyBPC) mutations.w6 Although MyBPC disease appears benign in that presentation is in the later decades, once disease develops patients are at risk of all the recognised complications of HCM including arrhythmia, stroke, and sudden …

HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes

Developed in partnership with the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology, and the Asia Pacific Heart Rhythm Society (APHRS); and in collaboration with the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the Pediatric and Congenital Electrophysiology Society (PACES) and the Association for European Pediatric and Congenital Cardiology (AEPC).

Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death.

The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors.

The magnitude of sudden cardiac death in the young: a death certificate-based review in England and Wales

AIMS In the UK, the true impact of cardiac and sudden death in the young (<or=35 years) is speculative. The authors critically appraised the office of national statistics (ONS) data for causes of death in the 1-34 years age group in England and Wales in an attempt to present an estimate of the incidence of such deaths and their underlying causes. METHODS AND RESULTS The investigators analysed the ONS mortality data for 2002-2005, inclusive. International classification of diseases-10 codes representing possible cardiac deaths were selected and divided into four classes; A1: definite cardiac deaths with no structural heart disease identified at post-mortem, A2: definite cardiac deaths with structural heart disease identified at post-mortem, A3: definite cardiac deaths with indeterminate cause, and B: possible cardiac deaths. Analysis of the data revealed an average of 419 (SD 16.5) definite cardiac deaths per annum (Class A1 + A2 + A3) equating to 1.8 per 100,000 per year (SD 0.08) or 8 deaths/week. There were also 433 (SD 6.2) deaths per year in class B which comprised primarily of deaths from drowning and epileptic seizures. The most prevalent causes were ischaemic heart disease (33.5%), cardiomyopathies (27%), sudden arrhythmic death syndrome (14%), myocarditis (11%), valvular heart disease (5%), and hypertensive cardiomyopathy (2%). CONCLUSION Our findings suggest that the number of cardiac and sudden deaths in the young identified is sufficiently high to command attention even without the inclusion of potential misclassifications (Class B). Awareness of such deaths among primary-care physicians, pathologists, and coroners should be raised to ensure that those at risk are identified and further tragedies are avoided.