BASIC SCIENCE
Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat
Christophe Boixel, PhD*,
Vincent Fontaine, PhD*,
Catherine Rücker-Martin, PhD ,
Paul Milliez, MD ,
Liliane Louedec, MS*,
Jean-Baptiste Michel, MD, PhD*,
Marie-Paule Jacob, PhD* and
Stéphane N. Hatem, MD, PhD* ,*
* INSERM Unité 460, Paris, France
Centre d’Exploration Fonctionnelle Intégrée Hôpital Xavier Bichat, Paris, France
CNRS-UMR 8078, Hôpital Marie Lannelongue, 92350 Le Plessis Robinson, France
INSERM Unité 572, Hôpital Lariboisière, Paris, France
Manuscript received October 13, 2002;
revised manuscript received January 7, 2003,
accepted February 6, 2003.
* Reprint requests and correspondence: Dr. Stéphane Hatem, INSERM Unité 460, Faculté de Médecine Bichat-Claude Bernard, 46 rue Henri Huchard, 75018, Paris, France.
hatem{at}bichat.inserm.fr
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.
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Abbreviations and Acronyms
| | 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 |
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