title: Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations.
abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24-/-mouse model of HGPS. Challenge of Zmpste24-/-mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24-/-cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24-/-progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.
authors: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
authors: José
authors: J
authors: Rivera-Torres
authors: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.|Group Electrophysiology and Bioengineering (GEB), Information and Communication Technologies Institute (ITACA), Universitat Politècnica de València, 46022 Valencia, Spain.|Department of Physiology, Facultad de Medicina y Odontología, Universidad de Valencia, 46010 Valencia, Spain.
authors: Conrado J
authors: CJ
authors: Calvo
authors: Institut de Investigació Biomedica Sant Pau, Hospital de Sant Pau, 08025 Barcelona, Spain.
authors: Anna
authors: A
authors: Llach
authors: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.|Cardiac Imaging Unit, Cardiology Department, Hospital Universitario La Paz, IdiPaz, 28046 Madrid, Spain.
authors: Gabriela
authors: G
authors: Guzmán-Martínez
authors: Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
authors: Ricardo
authors: R
authors: Caballero
authors: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
authors: Cristina
authors: C
authors: González-Gómez
authors: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.|Servicio de Cardiología, Hospital de la Princesa, 28006 Madrid, Spain.
authors: Luis J
authors: LJ
authors: Jiménez-Borreguero
authors: Department of Animal Biology, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain.|Centro Andaluz de Nanomedicina y Biotecnología (BIONAND), Junta de Andalucía, Universidad de Málaga, 29590 Campanillas, Spain.
authors: Juan A
authors: JA
authors: Guadix
authors: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors: Fernando G
authors: FG
authors: Osorio
authors: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors: Carlos
authors: C
authors: López-Otín
authors: Institut de Investigació Biomedica Sant Pau, Hospital de Sant Pau, 08025 Barcelona, Spain.|Cardiovascular Research Center, Hospital de Sant Pau, 08025 Barcelona, Spain.
authors: Adela
authors: A
authors: Herraiz-Martínez
authors: Institut de Investigació Biomedica Sant Pau, Hospital de Sant Pau, 08025 Barcelona, Spain.|Cardiovascular Research Center, Hospital de Sant Pau, 08025 Barcelona, Spain.
authors: Nuria
authors: N
authors: Cabello
authors: Automatic Control Department, Universitat Politécnica de Catalunya, 08034 Barcelona, Spain.
authors: Alex
authors: A
authors: Vallmitjana
authors: Automatic Control Department, Universitat Politécnica de Catalunya, 08034 Barcelona, Spain.
authors: Raul
authors: R
authors: Benítez
authors: Department of Pediatrics, Alpert Medical School of Brown University, Providence, RI 02903.|Department of Pediatrics, Hasbro Children's Hospital, Providence, RI 02903.|Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Leslie B
authors: LB
authors: Gordon
authors: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.|Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.|Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109-2800.
authors: José
authors: 0000-0003-0080-3500
authors: J
authors: Jalife
authors: Department of Animal Biology, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain.|Centro Andaluz de Nanomedicina y Biotecnología (BIONAND), Junta de Andalucía, Universidad de Málaga, 29590 Campanillas, Spain.
authors: José M
authors: JM
authors: Pérez-Pomares
authors: Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
authors: Juan
authors: J
authors: Tamargo
authors: Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
authors: Eva
authors: E
authors: Delpón
authors: Institut de Investigació Biomedica Sant Pau, Hospital de Sant Pau, 08025 Barcelona, Spain.|Cardiovascular Research Center, Hospital de Sant Pau, 08025 Barcelona, Spain.
authors: Leif
authors: L
authors: Hove-Madsen
authors: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.|Department of Cardiology, Cardiac Electrophysiology Unit, Hospital Clínico San Carlos, 28040 Madrid, Spain.
authors: David
authors: D
authors: Filgueiras-Rama
authors: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; vandres@cnic.es.
authors: Vicente
authors: V
authors: Andrés
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology; D000075224:Cardiac Conduction System Disease / Q000378:metabolism / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D018031:Connexin 43 / Q000378:metabolism / Q000502:physiology; D005260:Female; D006321:Heart / Q000502:physiology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D034881:Nuclear Lamina / Q000502:physiology; D011371:Progeria / Q000378:metabolism / Q000503:physiopathology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D055815:Young Adult
chemical_list: D018031:Connexin 43; D008565:Membrane Proteins; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse; D002118:Calcium
keywords: Hutchinson–Gilford progeria syndrome; calcium handling; connexin43; prelamin A; progerin