Charles I. Berul

HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)

Michael J. Ackerman, MD, PhD, Silvia G. Priori, MD, PhD, Stephan Willems, MD, PhD, Charles Berul, MD, FHRS, CCDS, Ramon Brugada, MD, PhD, Hugh Calkins, MD, FHRS, CCDS, A. John Camm, MD, FHRS, Patrick T. Ellinor, MD, PhD, Michael Gollob, MD, Robert Hamilton, MD, CCDS, Ray E. Hershberger, MD, Daniel P. Judge, MD, Hervè Le Marec, MD, William J. McKenna, MD, Eric Schulze-Bahr, MD, PhD, Chris Semsarian, MBBS, PhD, Jeffrey A. Towbin, MD, Hugh Watkins, MD, PhD, Arthur Wilde, MD, PhD, Christian Wolpert, MD, Douglas P. Zipes, MD, FHRS

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).

HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies

This international consensus statement provides the state of genetic testing for the channelopathies and cardiomyopathies. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the use and role of genetic testing for these potentially heritable cardiac conditions. This document focuses primarily on the state of genetic testing for the 13 distinct entities detailed and the relative diagnostic, prognostic, and therapeutic impact of the genetic test result for each entity. It does not focus on the therapeutic management of the various channelopathies and cardiomyopathies. Treatment/management issues are only discussed for those diseases (i.e., LQTS, HCM, DCM + CCD, RCM) in which the genetic test result could potentially influence treatment considerations.nnWriting recommendations for genetic diseases require adaptation of the methodology normally adopted to prepare guidelines for clinical practice. Documents produced by other scientific societies have acknowledged the need to define the criteria used to rank the strength of recommendation for genetic diseases.1nnThe most obvious difference is that randomized and/or blinded studies do not exist. Instead, most of the available data are derived from registries that have followed patients and recorded outcome information. The authors of this statement have therefore defined specific criteria for Class I, Class IIa or b, and Class III recommendations and have used the conventional language adopted by AHA/ACC/ESC Guidelines to express each class. All recommendations are level of evidence (LOE) C (i.e., based on experts opinions).nnA Class I recommendation ( “is recommended” ) was applied for genetic testing in index cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a genetic test is high (likelihood of positive result >40% and signal/noise ratio >10; Tablexa03), AND/OR when …

Transgenic Mice Overexpressing Mutant PRKAG2 Define the Cause of Wolff-Parkinson-White Syndrome in Glycogen Storage Cardiomyopathy

Background—Mutations in the &ggr;2 subunit (PRKAG2) of AMP-activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and electrophysiological abnormalities: Wolff-Parkinson-White syndrome (WPW) and progressive degenerative conduction system disease. Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance. Methods and Results—To elucidate the mechanism by which PRKAG2 mutations produce hypertrophy with electrophysiological abnormalities, we constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiological testing demonstrated alternative atrioventricular conduction pathways consistent with WPW. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation. Conclusions—Our data establish PRKAG2 mutations as a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiological findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe, Danon, and other glycogen storage diseases.

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.

In Vivo Cardiac Electrophysiology Studies in the Mouse

BACKGROUNDnThis report describes a novel in vivo mouse epicardial cardiac electrophysiology study based on clinical protocols used to evaluate cardiac conduction in human patients. The technique allows extensive electrophysiological evaluation, including the response to pacing, programmed stimulation, and pharmacological agents.nnnMETHODS AND RESULTSnSurface six-lead ECG data from 18 C57BL/6J mice are presented. Normal cardiac conduction properties for 14 of 18 mice that underwent the procedure are summarized, including determination of sinus node recovery times, AV conduction properties, and atrial, AV, and ventricular effective refractory periods. A subset of six mice was studied after the administration of either procainamide (n = 3) or quinidine (n = 3). All animals in the procainamide group developed either second-degree or complete AV block spontaneously. The sinus cycle length and refractory periods prolonged on procainamide or quinidine, but no tachyarrhythmias could be induced with atrial or ventricular programmed stimulation.nnnCONCLUSIONSnThis mouse electrophysiology method allows rapid assessment of the conduction properties of the murine heart. The ability to analyze cardiac conduction in normal and transgenic mice provides a powerful tool for examining molecular electrophysiological mechanisms in normal physiology and disease states.

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).

The National ICD Registry Report: Version 2.1 including leads and pediatrics for years 2010 and 2011

Mark S. Kremers, MD, FHRS, Stephen C. Hammill, MD, FHRS, Charles I. Berul, MD, FHRS, Christina Koutras, RN, Jeptha S. Curtis, MD, Yongfei Wang, MS, Jim Beachy, RCIS, Laura Blum Meisnere, MA, Del M. Conyers, MPH, Matthew R. Reynolds, MD, Paul A. Heidenreich, MD, Sana M. Al-Khatib, MD, MHS, FHRS, Ileana L. Pina, MD, MPH, Kathleen Blake, MD, MPH, FHRS, Mary Norine Walsh, MD, Bruce L. Wilkoff, MD, FHRS, Alaa Shalaby, MD, FHRS, Frederick A. Masoudi, MD, MSPH, John Rumsfeld, MD, PhD

Comparison of frequency of complications of implantable cardioverter-defibrillators in children versus adults

Compared with adults patients (n = 309) receiving implantable cardioverter-defibrillators at the same institution, pediatric patients (n = 11) exhibited a trend toward lower defibrillation thresholds. At follow-up of 29 +/- 17 months, the incidence of recurrent arrhythmias was similar, but lead revisions and device infections were more common in the pediatric patients.

Screening for Sudden Cardiac Death in the Young: Report From a National Heart, Lung, and Blood Institute Working Group

Sudden cardiac death (SCD) in the young (SCDY) has a devastating impact on families, care providers, and the community and attracts significant public and media attention. Sudden cardiac death is defined as an abrupt and unexpected death due to a cardiovascular cause, typically occurring 1 hour from the onset of symptoms. Depending on the source, “young” is variably defined as those less than 25, 30, 35, or 40 years of age. Estimates of the incidence of SCDY (not including infants) vary broadly from 0.6 to 6.2 per 100 000 persons. 1–3 Sudden infant death syndrome (SIDS) may be related to SCD in some infants. Sudden infant death syndrome is defined as the sudden death of an infant 1 year of age that cannot be explained after a thorough investigation is conducted, including an autopsy, death scene evaluation, and review of the clinical history. The incidence of SIDS ranges from 50 to 100 in 100 000,4 and emerging data suggest that as many as 10% to 15% of SIDS deaths are associated with functional cardiac ion channelopathy gene variants.5 The most common diagnoses that increase risk for SCDY include hypertrophic cardiomyopathy (HCM), coronary artery anomalies of wrong sinus origin, myocarditis, arrhythmogenic right ventricular cardiomyopathy, and ion channelopathies.6 The latter category includes hereditary diseases such as the congenital long-QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, among other less common channelopathies. These diseases are typically undetected before the SCD event. Estimated prevalence rates of these conditions range from 1 per 500 persons for HCM to 1 per 2500 for the LQTS. SCD related to these diagnoses has been documented in infancy and during competitive athletics. In addition, prescription stimulant use for treatment of attention deficit hyperactivity disorder (ADHD) has been postulated to be a trigger for SCD.7,8 Sudden cardiac death in the young is a critical public health issue. A young life cut short represents a devastating event for families, and is associated with many lost productive years. There is significant dissonance among experts in the field about the best approach to prevent SCDY in the United States. Some experts support the implementation of largescale cardiovascular screening programs in infants, in athletes, or in all children to identify at-risk individuals in an effort to prevent SCDY. Cardiovascular screening for SCDY typically involves the addition of an ECG to the current standard of care of history and physical examination. Echocardiography and genetic testing represent alternative or additional screening modalities. Observational data from the Veneto region of Italy suggest that ECG screening can successfully identify at-risk cardiovascular diseases and dramatically reduce the incidence of SCD in competitive athletes.9,10 Proponents of ECG screening in the United States suggest that it can be effective, feasible, and cost-effective. 11 Critics of ECG screening cite a lack of evidence to support its effectiveness or feasibility in the United States; lack of clinical accuracy; cost implications; and the potential clinical, financial, and emotional consequences of falsepositive screening test results. 12 Cost estimates for a national ECG screening program in the United States for