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The aim of the study: To show the influence of clinical and genetic factors on warfarin dosage during induction and long-term treatment in patients who followed heart valve surgery. The objectives of the study: 1. To determine the impact of amiodarone usage on warfarin dosage after heart valve surgery during induction and long-term treatment. 2. To evaluate the influence of CYPC9 and VKORC1 genetic polymorphism on warfarin dosage after heart valve surgery durint induction and long-term treatment. 3. To determine the impact of CYP4F2 rs1558139 gene polymorphism on warfarin dosage after heart valve surgery durint induction and long-term treatment. Objects ant methods: This study involved 91 patient who reached stable warfarin dosage (the therapeutic range of INR (from 2 to 3.5) was achieved and maintained for two days of treatment) during discharge from the hospital. Totally 72 patients, who used warfarin for at least 3 months, were included into the further study. Study involved 38 (52.8 %) men and 34 (47.2 %) women. DNA extraction, DNA quality assessment and real-time polymerase chain reaction (RT-PCR) were performed at the laboratory of Molecular Cardiology of LUHS.Prevalence of genotypes is presented in % (percent). Warfarin dosage is presented as mean ±SD. A p value

Objective and tasks. To evaluate and to determine whether CYP2C9 *2, *3, VKORC1 *2, *3 and CYP4F2 G1347A genotypes and clinical factors contribute to warfarin dosage in patients after heart valve surgeries. Methods. During the initiation of warfarin therapy, 175 patients, who had heart valve surgeries, were included into the study. During the long term treatment, totally 113 patients were analyzed. Patient anthropometric, clinical data (biochemical tests, used medications, addictions) and patient INR were obtained from the case histories. Genomic DNA was extracted from peripheral blood. The real – time polymerase chain reaction was used to detect the CYP2C9 * 2 (rs1799853) and *3 (rs1057910), VKORC1 *2 (rs9934438), VKORC1 *3 (rs7294) and CYP4F2 G1347A (rs2108622) genotypes. Statistical analysis. Results are presented as a mean and standard deviation (mean ± SD). A p≤0,05 was taken as statistically significant. Frequency of genotypes and alleles in patient’s sample is presented as % (percent). Results. The patients, users of amiodarone, required lower dosages of warfarin during treatment initiation, as compared to the non-users. During the long – term treatment period, the users of torasemide, calcium channel blockers and benzodiazepines, required lower warfarin dosages as compared to non-users of these drugs. During the long term treatment, patients with elevated creatinine or elevated alkaline phosphatase activity, required lower dosages of warfarin as compared to the patients with normal levels of these enzymes. Patients with such addictions (smoking and alcohol use) required higher dosages of warfarin. Besides the clinical factors, warfarin dosage was also influenced by these genetic variants (both at initiation of the warfarin therapy and during the long term treatment): CYP2C9*1*3 heterozygotes used lower warfarin dosages as compared to the wild-type homozygotes, VKORC1 C1173C carriers required higher dosages of warfarin than comparing to C/T and T/T genotype carriers, VKORC1 G3730G carriers required lower dosages of warfarin compared to A/A genotype carriers. The carriers of CYP4F2 A1347A required higher warfarin dosages, as compared to CYP4F2 G/G cariers, but only at initiation of warfarin therapy. Conclusions: Dosage of warfarin is influenced by such a clinical factors as the activity of plasma serum creatinine, the activity of alkaline phosphatase, medications - amiodarone, torasemide, calcium channel blockers, benzodiazepines, patient addictions (smoking, alcohol consumption). The genotypes CYP2C9 * 1 * 3, VKORC1 C1173T, VKORC1 G3730A and CYP4F2 G1347A are also significant in determining warfarin dosage.