Clinical trial NCT00484406: MMP Polymorphisms and Acute Coronary Syndromes
Official title: Matrix Metalloproteinase Genetic Polymorphisms and Outcome of Non-ST Elevated Acute Coronary Syndromes
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Unstable Angina
Keywords: Matrix Metalloproteinases
Atherosclerosis
Genetic polymorphism
Acute coronary syndromes
Lead sponsor: University of Trieste
Sponsor class: OTHER
First posted: 2007-06-08
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: DEFINED_POPULATION
Time perspective: PROSPECTIVE

Brief summary: Some Matrix Metalloproteases, proteases degrading the extracellular matrix, play a relevant role in structure and stability of atherosclerotic plaques. Atherosclerotic plaques triggering acute coronary syndromes show increased expression of MMP-1, MMP-3 and MMP-9. Regulation of these MMPs is plaid by genetic polymorphisms, G+/G- at -1563 for MMP-1, 4A/5A- at -1612 for MMP-3, and a microsatellite (13-27 CA repeats around -90) for MMP-9.

It is conceivable that these polymorphisms correlate with the clinical outcome of acute coronary syndromes, particularly with those without ST segment Elevation (NSTEACS).

Detailed description: Non-ST elevation acute coronary syndrome (NSTEACS) is a syndrome encompassing a spectrum of clinical manifestations between ischemic heart disease and acute myocardial infarction. It represents an important cause of morbidity and hospitalization in western countries: its incidence is estimated around 2/1000 subjects/year and about 10% of patients with acute coronary syndrome develop an acute myocardial infarction within 6 months. Another reason of concern is that patients require an invasive treatment, usually PTCA or CABG. ACS encompasses features of both an inflammatory and thrombotic disease; their abnormalities could be critical for evolution and complication of acute coronary syndrome.

Many inflammatory and coagulation indicators have been investigated, although the critical factors responsible for complications in NSTEACS remain elusive.

Matrix remodeling and consequent erosion or fissuration of the unstable plaque is supposed to be a key step of the development of acute coronary syndromes.

Neutral matrix metalloproteinases 1, 3 and 9 have been demonstrated to be actively produced in atherosclerotic tissue, compared to unaffected arteries. Mechanisms responsible for such increased expression might be related to inflammation, but also genetic regulation could account for an increased expression leading to a different clinical outcome of the syndrome.

Genetic polymorphisms are described for all three MMPs involved in ACS. MMP-1 insertion of a G in position creates an ets binding site that induces an eight times increase of the synthesis rate. For MMP-3 (stromelysin) polymorphism, a deletion of an A (adenosine) in position -1171 doubles the transcription activity and has been recently associated with acute myocardial infarction and progression of coronary stenosis. In MMP-9 a more complex polymorphism involves a microsatellite (AC) repeat in position -90 to -131. The mechanism leading to increased MMP-9 expression is probably related to the transition to Z-DNA within the microsatellite, which eases transcription. In vitro studies show that the longer the tandem repeats sequence, the higher the transcription.

No studies on metalloproteinase polymorphism in NSTEACS have been carried out, so far.

This study has been planned to assess if patients admitted to the hospital for NSTEACS could be associated to a different in hospital clinical outcome according to the genetic polymorphism of these proteases.

Eligibility criteria: Inclusion Criteria:

* non ST elevation acute coronary syndrome (NSTE ACS)

Exclusion Criteria:

* STE acute myocardial infarction

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Pordenone
country: Italy
facility: Azienda per i Servizi Sanitari n.6 "FRIULI OCCIDENTALE"
city: Trieste
country: Italy
facility: Clinica Medica - University of Trieste
Study officials:
affiliation: University of Trieste, ITALY
name: Nicola FIOTTI, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Trieste, ITALY
name: Carlo Giansante, MD
role: STUDY_CHAIR
References:
citation: Fiotti N, Altamura N, Fisicaro M, Carraro N, Uxa L, Grassi G, Torelli L, Gobbato R, Guarnieri G, Baxter BT, Giansante C. MMP-9 microsatellite polymorphism and susceptibility to carotid arteries atherosclerosis. Arterioscler Thromb Vasc Biol. 2006 Jun;26(6):1330-6. doi: 10.1161/01.ATV.0000219233.31702.c9. Epub 2006 Mar 30.
citation: Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994 Dec;94(6):2493-503. doi: 10.1172/JCI117619.
citation: Pollanen PJ, Lehtimaki T, Mikkelsson J, Ilveskoski E, Kunnas T, Perola M, Penttila A, Mattila KM, Nikkari ST, Syrjakoski K, Karhunen PJ. Matrix metalloproteinase3 and 9 gene promoter polymorphisms: joint action of two loci as a risk factor for coronary artery complicated plaques. Atherosclerosis. 2005 May;180(1):73-8. doi: 10.1016/j.atherosclerosis.2004.10.041. Epub 2004 Dec 18.
citation: Terashima M, Akita H, Kanazawa K, Inoue N, Yamada S, Ito K, Matsuda Y, Takai E, Iwai C, Kurogane H, Yoshida Y, Yokoyama M. Stromelysin promoter 5A/6A polymorphism is associated with acute myocardial infarction. Circulation. 1999 Jun 1;99(21):2717-9. doi: 10.1161/01.cir.99.21.2717.
citation: Fiotti N, Moretti ME, Bussani R, Altamura N, Zamolo F, Gerloni R, Ukovich L, Ober E, Silvestri F, Grassi G, Adovasio R, Giansante C. Features of vulnerable plaques and clinical outcome of UA/NSTEMI: Relationship with matrix metalloproteinase functional polymorphisms. Atherosclerosis. 2011 Mar;215(1):153-9. doi: 10.1016/j.atherosclerosis.2010.12.010. Epub 2010 Dec 21.