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Colonna, Stefania (2008) Identification of High Risk Coronary Artery Disease patient by Molecular Techiniques: the MEF-2A paradigm. [Ph.D. thesis]

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Abstract (english)

Background. The coronary artery disease (CAD) and its clinical manifestations (angina and myocardial infarction, MI) are the first cause of death in most industrialized societies. Current guidelines used to detect those susceptible to heart attack fail to identifying many high-risk individuals. In recent years, a number of new candidate risk factors or markers have been proposed. Among risk factors, family history is one of the most significant independent risk factor for CAD/MI. Only one disease-causing gene, myocyte enhancer factor-2 (MEF2A), encoding a member of the MEF2 family of transcription factors, has been identified for primary CAD and MI without other accompanying clinical feature
Aim of the Study. Available evidences suggest that MEF2A plays a role in vascular ontogeny and shows its predominant expression in the coronary artery endothelium. Considering the pivotal role played by the latter in atherogenesis, we investigated:
1. the prevalence of MEF2A deleted gene in a large case-control study (GENICA Study)
2. if the deletion might be associated with coronary artery structural and functional abnormalities;
3. if it might be associated with widespread endothelial dysfunction;
4. if either one or the other or both alterations might eventually result into clinically relevant coronary artery disease.
Methods. We developed techniques suitable high throughout genotyping based on FRET () and HMRA (). After validation of these techniques vs sequencing, we prospectively genotyped 2 cohorts of healthy subjects, a cohort of primary hypertensive patients and the vast cohort of the GENICA Study.
Results. In the present study, the prevalence rate of the MEF2A deletion resulted 0 individuals in healthy subjects of 2 cohorts (n= 170 pts) and in primary hypertensive patients (n=131 pts); to be very low in the vast majority of the GENICA Study (n=1141 pts) cohort. In this study we found the MEF2A deletion in only one of 1142 consecutive patients referred for coronary artery angiography. Therefore, the prevalence in the latter was 8.7 per 10.000 (<1 ‰) patients.
Then we investigated of his pedigree and found that the deletion has been transmitted to one of the subject of the third generation. The MEF2A deleted-gene patient showed a clear endothelial impairment, and, at cardiac Magnetic Resonance a first passage hypoperfusion in the postero-lateral wall with a late enhancement as a post-ischemic fibrotic tissue.
Discussion. To our knowledge, our pedigree is the first to be identified in Europe. The significance of identification of MEF2A as the first disease-causing gene for CAD and MI makes genetic testing possible for many individuals with a very high risk for CAD and MI. and wise to extend screening to pedigree of subjects with acute myocardial infarct or acute coronary syndrome and few or no risk factors.

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EPrint type:Ph.D. thesis
Tutor:Pessina, Achille Cesare
Supervisor:Rossi, Gian Paolo
Data di deposito della tesi:31 January 2008
Anno di Pubblicazione:31 January 2008
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Medicina Clinica e Sperimentale
Codice ID:861
Depositato il:11 Sep 2008
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