LETTER TO THE EDITOR
Matrix metalloproteinases in atrial fibrillation
Francisco Marín, MD, PhD,
Vanessa Roldán, MD, PhD,
Vicente Climent, MD and
Gregory Y. H. Lip, MD, FACC, FESC
University Department of Medicine, City Hospital, Birmingham B18 7QH, United Kingdom
g.y.h.lip{at}bham.ac.uk
We read with great interest the study by Boixel et al. (1), which examines the importance of matrix metalloproteinase (MMP) system in atrial remodeling in a rat model of heart failure. The investigators demonstrate the up-regulation of MMP-2 and MMP-9 in the atria with marked structural abnormalities, but there were no significant differences in tissue inhibitors of MMP (TIMP) activity.
The clinical significance of the report by Boixel et al. (1) requires clarification in a (human) patient population. We recently explored plasma levels of MMP-1 and TIMP-1 in 48 consecutive patients with chronic nonrheumatic atrial fibrillation (AF) (2) and found evidence of impaired matrix degradation, with lower levels of MMP-1 and increased levels of TIMP-1 compared with controls. However, these values were not independently associated with the presence of AF on multivariate analysis. Instead, clinical (i.e., age, ischemic heart disease, or hypertension) and echocardiographic variables (end-diastolic left ventricular diameter or left ventricular mass index) were found to be independently associated with MMPs. In a preliminary study, decreased MMP-1 activity was found in the atria of AF patients undergoing open-heart surgery (3).
There are controversial data whether structural changes in the atria are related to AF (4,5) or to underlying diseases (6,7). Our findings (2) and those of Boixel et al. (1) suggest that increased interstitial fibrosis in atrial tissue is more likely due to underlying comorbidities, like hypertension, ischemic heart disease, or uncontrolled heart failure (circumstances associated with high risk to develop AF), than to the presence of arrhythmia itself. Moreover, experimental data suggest that underlying diseases promote AF by causing atrial interstitial fibrosis (8). Certainly, decreased concentration of MMP-1 (the most important enzyme in the extracellullar degradation of collagen types I and III) with raised levels of TIMP-1 have been observed in hypertensive patients (9). In this setting, TIMP-1 has been recently proposed as a noninvasive marker of fibrosis in a large cohort of untreated hypertensive subjects (10).
Finally, the possible relationship of the MMP system to the thromboembolic risk in AF merits exploration. For example, an independent relationship was observed between the MMP system and the prothrombotic state in AF (as assessed by prothrombin fragment 1 + 2 levels) (2).
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1. 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]
2. Marín F, Roldán V, Climent V, García A, Marco P, Lip GYH. Is thrombogenesis in atrial fibrillation related to matrix metalloproteinase-1 and its inhibitor, TIMP-1? Stroke. 2003;34:1181–1186[Abstract/Free Full Text]
3. Goette A, Nepple K, Arndt M, et al. Atrial expression of matrix-metalloproteinases in fibrillating human atria (abstr). Eur Heart J. 2003;23(Suppl):138
4. Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M. Structural changes of atrial fibrillation due to sustained atrial fibrillation. Circulation. 1997;96:3157–3163[Abstract/Free Full Text]
5. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation. 1997;96:1180–1184[Abstract/Free Full Text]
6. Schotten U, Ausma J, Stellbrink C, et al. Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation. Circulation. 2001;103:691–698[Abstract/Free Full Text]
7. Shirani J, Aleddini J. Structural remodeling of the atrial appendage in patients with chronic non-valvular atrial fibrillation: implications for thrombus formation, systemic embolism, and assessment by transesophageal echocardiography. Cardiovasc Pathol. 2000;9:95–101[CrossRef][Medline]
8. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs. Atrial remodeling of a different sort. Circulation. 1999;100:87–95[Abstract/Free Full Text]
9. Laviades C, Varon N, Fernández J, et al. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation. 1998;97:1708–1715[Abstract/Free Full Text]
10. Lindsay MM, Maxwell P, Dunn FG. A marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension. 2002;40:136–141[Abstract/Free Full Text]
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