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Defective Intercellular Adhesion Complex in Myocardium Predisposes to Infarct Rupture in Humans

Susanne W.M. van den Borne, MD^_*, Jagat Narula, MD, PhD, FACC, J. Willem Voncken, PhD, Peter M. Lijnen, BSc^_*, Helena T.M. Vervoort-Peters, BSc^_*, Vivian E.H. Dahlmans, BSc, Jos F.M. Smits, PhD^_*, Mat J.A.P. Daemen, MD, PhD^_* and W. Matthijs Blankesteijn, PhD^_*,_*

^_* Department of Pharmacology and Toxicology and Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
Department of Molecular Genetics, Research Institute for Growth and Development, Maastricht University, Maastricht, the Netherlands
Division of Cardiology, University of California School of Medicine, Irvine, California.

Manuscript received September 18, 2007; revised manuscript received February 1, 2008, accepted February 20, 2008.

^_* Reprint requests and correspondence: Dr. W. Matthijs Blankesteijn, Department of Pharmacology and Toxicology, CARIM, Maastricht University, 50 Universiteitssingel, P.O. Box 616, 6200 MD Maastricht, the Netherlands. (Email: wm.blankesteijn{at}farmaco.unimaas.nl).

Objectives: Our goal was to evaluate intercellular adhesion complex proteins in myocardium in human infarct rupture.

Background: Infarct rupture, a fatal complication of myocardial infarction (MI), has been attributed to a defective cell adhesion complex in a transgenic mouse model.

Methods: Heart samples were collected from autopsies from infarct rupture and control (nonrupture) MI patients. Both infarcted and remote areas were included. Cell adhesion proteins including E-catenin, β-catenin, -catenin, and N-cadherin were characterized by immunohistochemistry and immunoblotting. Genetic analysis was undertaken to evaluate mutations and polymorphisms in the E-catenin gene. In addition, infarct rupture was studied in transgenic mice heterozygous for E-catenin C-terminal deficiency, mimicking the situation in human infarct rupture patients.

Results: No E-catenin was detected in 70% of remote samples of infarct rupture hearts compared with 20% in control MI by immunohistochemistry. The immunoblot analysis confirmed a significant reduction in remote areas, and complete absence of E-catenin in infarct areas from infarct rupture patients. No mutation or polymorphism of the E-catenin gene was discovered. Other cell adhesion proteins were not significantly affected in remote areas of infarct rupture hearts. Three-fourths of the heterozygous E-catenin C-terminal truncated mice died of infarct rupture, compared with one-fourth of the wild-type littermates.

Conclusions: The data show a reduced expression and defective localization of E-catenin in the intercalated disc region in patients dying of infarct rupture. The mechanism of lower expression of E-catenin remains to be elucidated.

Abbreviations and Acronyms   ICD = intercalated disc   LV = left ventricle/ventricular   MI = myocardial infarction   PCR = polymerase chain reaction   SNP = single nucleotide polymorphism

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