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Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):E7250-E7259. Epub 2016 Oct 31.

Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations.

Author information

1
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
2
Group Electrophysiology and Bioengineering (GEB), Information and Communication Technologies Institute (ITACA), Universitat Politècnica de València, 46022 Valencia, Spain.
3
Department of Physiology, Facultad de Medicina y Odontología, Universidad de Valencia, 46010 Valencia, Spain.
4
Institut de Investigació Biomedica Sant Pau, Hospital de Sant Pau, 08025 Barcelona, Spain.
5
Cardiac Imaging Unit, Cardiology Department, Hospital Universitario La Paz, IdiPaz, 28046 Madrid, Spain.
6
Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
7
Servicio de Cardiología, Hospital de la Princesa, 28006 Madrid, Spain.
8
Department of Animal Biology, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29071 Málaga, Spain.
9
Centro Andaluz de Nanomedicina y Biotecnología (BIONAND), Junta de Andalucía, Universidad de Málaga, 29590 Campanillas, Spain.
10
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
11
Cardiovascular Research Center, Hospital de Sant Pau, 08025 Barcelona, Spain.
12
Automatic Control Department, Universitat Politécnica de Catalunya, 08034 Barcelona, Spain.
13
Department of Pediatrics, Alpert Medical School of Brown University, Providence, RI 02903.
14
Department of Pediatrics, Hasbro Children's Hospital, Providence, RI 02903.
15
Department of Anesthesia, Division of Critical Care Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
16
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
17
Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109-2800.
18
Department of Cardiology, Cardiac Electrophysiology Unit, Hospital Clínico San Carlos, 28040 Madrid, Spain.
19
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; vandres@cnic.es.

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.

KEYWORDS:

Hutchinson–Gilford progeria syndrome; calcium handling; connexin43; prelamin A; progerin

PMID:
27799555
PMCID:
PMC5135377
DOI:
10.1073/pnas.1603754113
[Indexed for MEDLINE]
Free PMC Article

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