LETTER TO THE EDITOR
Matrix metalloproteinases in atrial fibrillation: Reply
Christophe Boixel, PhD,
Vincent Fontaine, PhD,
Jean-Baptiste Michel, MD, PhD,
Marie-Paule Jacob, PhD and
Stéphane Hatem, MD
INSERM Unité 460, Faculté de Médecine Bichat-Claude Bernard, 46, rue Henri Huchard, 75018 Paris, France
hatem{at}bichat.inserm.fr
Marín and collaborators report that, in patients in atrial fibrillation (AF), plasma level of MMP-1 is decreased while that of TIMP-1 is increased, suggesting an impaired matrix degradation in this clinical setting (1). Because alteration in the MMP/TIMP system correlates with left ventricular mass and remodeling but not with AF, the investigators conclude that the atrial fibrosis is caused by the underlying diseases. This is in agreement with our studies in a rat model of heart failure with atrial dilation (2) or in human right appendages (3) showing that structural alterations of the atrial myocardium are associated with left ventricle dysfunction, independently of AF.
An apparent controversy exists between the decreased MMP-1 and increased TIMP-1 in plasma of patients in AF (1) and the up-regulation of MMP-2 and MMP-7 (and not MMP-9 see the letter of Marín et al) but not of TIMPs in our model (2). One explanation is probably that we studied protease activity in tissue and not in plasma. This point is crucial for MMP-7, which is anchored to cell basement membrane, thus preventing its diffusion and probably any increase in the plasma (4).
Myocardial fibrosis is a dynamic process during which normal collagen chains are degraded and replaced by fibrous interstitial deposits. The MMPs are involved both in matrix degradation and collagen synthesis (5). Thus, their up-regulation in dilated rat atria suggests an ongoing activation of processes leading to matrix remodeling. This may not be the case in patients with long-lasting history of AF and a therapeutically controlled hypertension or heart failure (1). A time-dependent MMP activation is well known during the progression of cardiopathies. Acute pressure overload induces myocardial MMP activation that normalizes with the prolongation of the pressure overload (6). Distinct regulations of the various MMPs may also occur during atrial remodeling. In dilated cardiomyopathy, the myocardial activity of MMP-1 is decreased while the activities of MMP-2, MMP-3, and MMP-9 are increased (7).
The study by Marín and colleagues raises an important point concerning the possibility of using in clinical practice MMP and TIMP plasma levels as indicators of atrial remodeling and the risk of thrombogenesis. Such an approach relies on the relevance of plasma changes of MMPs and TIMPs to the atrial remodeling. For instance, vascular cells are an important source of TIMP-1 and can also contribute to its increase during hypertension (8).
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References
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1. Marín F, Roldán V, Climent V, et al. Is thrombogenesis in atrial fibrillation related to matrix metalloproteinase-1 and its inhibitor, TIMP-1? Stroke. 2003;34:1181–1186[Abstract/Free Full Text]
2. Boixel C, Fontaine V, Rücker-Martin C, et al. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol. 2003;42:336–344[Abstract/Free Full Text]
3. Aimé-Sempé C, Folliguet T, Rücker-Martin C, et al. Myocardial cell death in fibrillating and dilated human right atria. J Am Coll Cardiol. 1999;34:1577–1586[Abstract/Free Full Text]
4. Yu WH, Woessner JF. Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase-7). J Biol Chem. 2000;275:4183–4191[Abstract/Free Full Text]
5. Gunja-Smith Z, Morales AR, Romanelli R, Woessner JF. Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy. Role of metalloproteinases and pyridinoline cross-links. Am J Pathol. 1996;148:1639–1648[Medline]
6. Nagatomo Y, Carabello BA, Coker ML, et al. Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control. Am J Physiol. 2000;278:H151–161
7. Spinale FG, Coker ML, Heung LJ, et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation. 2000;102:1944–1949[Abstract/Free Full Text]
8. Gonzales W, Fontaine V, Peuyo ME, et al. Molecular plasticity of vascular wall during N(G)-nitro-L-arginine methylester-induced hypertension: modulation of proinflammatory signal. Hypertension. 2000;36:103–109[Abstract/Free Full Text]
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