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CLINICAL RESEARCH: ACUTE MYOCARDIAL INFARCTION

A pharmacogenetic effect of factor XIII valine 34 leucine polymorphism on fibrinolytic therapy for acute myocardial infarction

Francisco Marín, MD, PhD^*, Rocío González-Conejero, PhD, Kaeng W. Lee, MRCP, Javier Corral, PhD, Vanessa Roldán, MD, PhD, Francisca López, MD^||, Francisco Sogorb, MD^*, Juan Caturla, MD, PhD^||, Gregory Y.H. Lip, MD, FESC, FACC and Vicente Vicente, MD, PhD^,*

^* Cardiology Department, Hospital General Universitario, Alicante, Spain
Centro de Hemodonación, Universidad de Murcia, Murcia, Spain
Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, England
Hematology Unit, Hospital de San Vicente, Alicante, Spain
^|| Intensive Care Unit, Hospital General Universitario, Alicante, Spain

Manuscript received July 29, 2004; revised manuscript received September 9, 2004, accepted September 20, 2004.

^* Reprint requests and correspondence: Prof. Vicente Vicente, Centro Regional de Hemodonación, Ronda de Garay s/n 30003, Murcia, Spain (Email: Vicente.Vicente{at}carm.es).

OBJECTIVES: The aim of this study was to evaluate the pharmacogenetic role of the factor XIII (FXIII) valine 34 leucine (Val34Leu) polymorphism in the fibrinolytic therapy of acute myocardial infarction (MI).

BACKGROUND: Fibrinolytic therapy is an established treatment for acute MI, but up to 40% of treated patients do not achieve optimal tissue reperfusion. The FXIII Val34Leu polymorphism is one of the most relevant functional polymorphisms described in the haemostatic system. The common Leu34 allele associates with an increased FXIII-transglutaminase activity, which results in an increased and faster rate of fibrin stabilization.

METHODS: We genotyped this polymorphism in 293 consecutive MI patients (62 ± 12 years; 231 males) from two different European populations. All patients were treated with standard doses of fibrinolytic drugs. Noninvasive assessment of the efficacy of coronary fibrinolysis was evaluated by serial electrocardiograms and creatine kinase time-activity curves. The clinical outcome was also re-evaluated at 24 h (death, reinfarction, or urgent revascularization).

RESULTS: Multivariate analysis showed that Leu34 carriers displayed a significantly less efficient fibrinolysis than carriers of Val/Val genotype (p = 0.021; odds ratio [OR] 1.90, 95% confidence interval [CI] 1.10 to 3.28). At 24 h, Leu34 allele carriers had the worst outcome (p = 0.006; OR 2.14, 95% CI 1.25 to 3.68). Interestingly, the combination of the Leu34 allele and nonsmoking status increased the risk of non-reperfusion criteria (p = 0.003, OR 3.77), and worse outcomes at 24 h (p = 0.001, OR 4.55).

CONCLUSIONS: In a large cohort of nonselected and consecutive acute MI patients from two different European populations, we show clinical evidence that the presence of the Leu34 allele reduces the efficacy of fibrinolytic therapy.

Abbreviations and Acronyms   CI = confidence interval   CK = creatine kinase   FXIII = factor XIII   Leu = leucine   MI = myocardial infarction   OR = odds ratio   PCI = percutaneous coronary intervention   Val = valine

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