Basic science
Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat

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Abstract

Objectives

The purpose of this study was to determine the pathogenic factors and molecular mechanisms involved in fibrosis of the atria.

Background

Fibrosis is an important component of the pathophysiology of atrial fibrillation, especially when the arrhythmia is associated with heart failure (HF) or atrial dilation.

Methods

We used a rat model of myocardial infarction (MI) complicated by various degrees of left ventricular dysfunction and atrial dilation to study fibrosis and matrix metalloproteinase (MMP) activity in the left atrial (LA) myocardium by means of histologic, Western blot, zymographic, and immunohistologic techniques.

Results

Three months after surgical ligature of the left coronary artery, 27 rats had a large MI, 12 were in mild HF, and 15 in severe HF. Both groups had LA enlargement at the echocardiography. Masson’s trichrome and picrosirius staining of tissue sections revealed marked fibrosis at the periphery of trabeculae and also surrounding myolytic myocytes, in both mild and severe HF. In mild HF, the activity and expression of the matrilysin MMP-7 were increased (122%), whereas in severe HF, both MMP-7 (211%) and the gelatinase MMP-2 (187%) were up-regulated. There were no changes in the expression or activity of MMP inhibitors, TIMP-1, -2, and -4. Immunostaining of cryosections showed that MMP-2 was present in the interstitial spaces, whereas MMP-7 accumulated in myolytic myocytes.

Conclusions

Hemodynamic overload of the atria is an important pathogenic factor of fibrosis; MMP-7 appears to be involved in the early stage of this tissue remodeling process.

Abbreviations

AF
atrial fibrillation
ANP
atrial natriuretic peptide
AU
arbitrary unit
HF
heart failure
LA
left atria/atrial
LV
left ventricle
MI
myocardial infarction
MMP
matrix metalloproteinase
RA
right atria/atrial
TIMP
tissue inhibitor of metalloproteinase

Cited by (0)

This study was supported by INSERM, the Société Française de Cardiologie, Servier Laboratory, Association Française contre les Myopathies, and Fondation de France. Drs. Boixel and Fontaine contributed equally to this work.