Angela Lopez-Sainz1, Fernando Dominguez2, Luis Rocha Lopes3, Juan Pablo Ochoa4, Roberto Barriales-Villa5, Vicente Climent6, Marijke Linschoten7, Coloma Tiron8, Chiara Chiriatti9, Nuno Marques10, Torsten B Rasmussen11, María Ángeles Espinosa12, Roy Beinart13, Giovanni Quarta14, Sergi Cesar15, Ella Field16, Jose M Garcia-Pinilla17, Zofia Bilinska18, Alison R Muir19, Angharad M Roberts20, Enrique Santas21, Esther Zorio22, Maria Luisa Peña-Peña23, Marina Navarro24, Adrian Fernandez25, Julian Palomino-Doza26, Olga Azevedo27, Massimiliano Lorenzini3, Maria I García-Álvarez6, Dina Bento10, Morten K Jensen11, Irene Méndez12, Laura Pezzoli14, Georgia Sarquella-Brugada28, Oscar Campuzano29, Esther Gonzalez-Lopez1, Jens Mogensen30, Juan Pablo Kaski16, Michael Arad13, Ramon Brugada8, Folkert W Asselbergs31, Lorenzo Monserrat4, Iacopo Olivotto9, Perry M Elliott3, Pablo Garcia-Pavia32. 1. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart. 2. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Myocardial Biology Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Electronic address: fdominguezrodriguez@gmail.com. 3. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Barts Heart Centre, St. Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom; Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, United Kingdom. 4. Cardiology Department, Health in Code, A Coruña, Spain. 5. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; Inherited Cardiovascular Diseases Unit, Cardiology Service, Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde, Instituto de Investigación Biomédica de A Coruña, Universidade da Coruña, A Coruña, Spain. 6. Cardiology Department, Hospital General Universitario de Alicante, Institute of Health and Biomedical Research, Alicante, Spain. 7. Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 8. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitari Dr. Josep Trueta, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain. 9. Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy. 10. Algarve Biomedical Center, Faro, Portugal; Hospital Universitário do Algarve, Faro, Portugal; Biomedical and Medicine Department, University of Algarve, Faro, Portugal. 11. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. 12. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 13. Leviev Heart Center, Sheba Medical Center and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 14. ASST Papa Giovanni XXIII, Bergamo, Italy. 15. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Arrhythmia, Inherited Cardiac Diseases and Sudden Death Unit, Pediatric Cardiology Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain. 16. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital and UCL Institute of Cardiovascular Science, London, United Kingdom. 17. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; Heart Failure and Familial Cardiomyopathies Unit, Cardiology Department, Hospital Universitario Virgen de la Victoria, IBIMA, Malaga, Spain. 18. Unit for Screening Studies in Inherited Cardiovascular Diseases, The Cardinal Stefan Wyszynski Institute of Cardiology, Warsaw, Poland. 19. Northern Ireland Inherited Cardiac Conditions Service, Belfast Health and Social Care Trust, Belfast, United Kingdom. 20. National Heart and Lung Institute, Imperial College London, London, United Kingdom; Cardiovascular Research Centre, Royal Brompton and Harefield NHS Foundation Trust London, London, United Kingdom. 21. Department of Cardiology, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain. 22. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; Inherited Cardiac Diseases and Sudden Death Unit, Department of Cardiology, Hospital Universitario y Politécnico La Fe, Instituto de Investigación Sanitaria La Fe, Valencia, Spain. 23. Inherited Cardiac Diseases and Cardiac Imaging Unit, Department of Cardiology, Hospital Universitario Virgen del Rocío, Seville, Spain. 24. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain. 25. Department of Ambulatory Cardiology, Favaloro Foundation University Hospital, Buenos Aires, Argentina. 26. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; Inherited Cardiac Diseases Unit, Cardiology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, Madrid, Spain. 27. Cardiology Department, Hospital Senhora da Oliveira, Guimarães, Portugal; European Reference Network on Hereditary Metabolic Disorders; Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal; Life and Health Sciences Research Institute/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal. 28. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Arrhythmia, Inherited Cardiac Diseases and Sudden Death Unit, Pediatric Cardiology Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain. 29. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Biochemistry and Molecular Genetics Department, Hospital Clinic, University of Barcelona-IDIBAPS, Barcelona, Spain. 30. Department of Cardiology, Odense University Hospital, Odense, Denmark. 31. Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom; Health Data Research UK and Institute of Health Informatics, University College London, London, United Kingdom. 32. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Universidad Francisco de Vitoria, Pozuelo de Alarcon, Spain. Electronic address: pablogpavia@yahoo.es.
Abstract
BACKGROUND: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.
BACKGROUND:PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS:PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Back Sternick Eduardo; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong-Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti Mac Intyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Pablo Ochoa Juan; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: J Arrhythm Date: 2022-05-31
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Eduardo Back Sternick; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti MacIntyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Juan Pablo Ochoa; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: Europace Date: 2022-09-01 Impact factor: 5.486
Authors: Yishay Wasserstrum; José M Larrañaga-Moreira; Cristina Martinez-Veira; Edward Itelman; Dor Lotan; Avi Sabbag; Rafael Kuperstein; Yael Peled; Dov Freimark; Roberto Barriales-Villa; Michael Arad Journal: ESC Heart Fail Date: 2022-04-30
Authors: Anna Witasp; Karin Luttropp; Abdul Rashid Qureshi; Peter Barany; Olof Heimbürger; Lars Wennberg; Tomas J Ekström; Paul G Shiels; Peter Stenvinkel; Louise Nordfors Journal: Sci Rep Date: 2022-01-10 Impact factor: 4.379
Authors: Luiz Pereira de Magalhães; Eduardo Faria Soares de Magalhães; Jussara de Oliveira Pinheiro; Alex Teixeira Guabiru; Francisco José Farias Borges Dos Reis; Roque Aras Journal: Arq Bras Cardiol Date: 2022-01 Impact factor: 2.000