The association between SCN5A, KCNQ1 and KCNE1 gene polymorphisms and complex ventricular arrhythmias in survivors of myocardial infarction.

BACKGROUND: Post-MI patients are highly susceptible to sudden cardiac arrest (SCA) and sudden cardiac death (SCD) resulting from ventricular arrhythmia (VA). The search for new clinical predictors to identify those patients who are at the highest risk of these events is therefore essential. Numerous data indicate that the presence of polymorphisms and mutations in the cardiac ion channel genes SCN5A, KCNQ1 and KCNE1 might serve as such a predictor. Since genetic alterations in these genes underlie congenital long QT syndrome (LQTS), which is associated with an increased occurrence of arrhythmic complications and SCD, we decided to verify how alterations in these genes contribute to QT interval abnormalities and consequently to VA, SCA and SCD in post-MI patients. AIM: To detect single nucleotide polymorphisms (SNP) in SCN5A, KCNQ1 and KCNE1 of post-MI patients, and to assess whether they are related to electrophysiological markers of cardiac arrhythmia (QT interval) and the clinical course. METHOD: The study group consisted of 100 patients (27 females, mean age 69 years) with documented MI 3 months before enrolment. All patients underwent baseline and (after 12 months) control examinations encompassing history, physical examination, basic laboratory analysis, resting 12-lead ECG, 24-hour 12-lead Holter ECG monitoring and echocardiography. Genetic tests were performed during baseline examination. RESULTS: In post-MI patients two exonic polymorphisms, H558R in SCN5A and S38G in KCNE1, and two intronic ones, in KCNQ1, were detected. H558R was associated with an increase in QT dispersion (QTd) at minimum and maximum heart rate and QT interval prolongation before premature ventricular beats (PVB), whereas S38G and intronic polymorphisms were related to an increase in QTd before PVB. None of the above polymorphisms was related to complex VA, SCA or SCD. CONCLUSION: The above polymorphisms were associated with abnormal repolarisation phase patterns in post-MI patients, which manifested in QT interval prolongation and QTd increase. There was no relationship between these polymorphisms and complex VA, SCA or SCD. The results show that not only exonic alterations but also intronic ones may affect the phenotype.

Novel KCNQ1 mutations in patients after myocardial infarction.

BACKGROUND: Patients after myocardial infarction (MI) are at greater risk of sudden cardiac death (SCD) than people in the overall population. The aim of this study was to detect mutations, including intronic ones, in the KCNQ1 gene coding for proteins of cardiac potassium channels and evaluate their possible effects on the clinical course in patients after MI. METHODS: The study group was composed of 100 Polish patients after MI, which included 27 women (mean age 69 years) and 73 men (mean age 67 years). All patients underwent clinical examinations and genetic tests. The genetic test results have been correlated with the clinical data. The following parameters have been chosen as endpoints for this survey: sudden cardiac arrest (SCA) or SCD, complex ventricular arrhythmia, QT interval and QT dispersion values assessed during 24-hour Holter ECG monitoring in relation to ventricular arrhythmias as well as the minimum and maximum heart rate (HR) observed during the examination. RESULTS: Six new mutations in the KCNQ1 gene: C2505734T, A2753831C in exons and C2505846A, G2753881A, T2755854C, T2755875G in introns. Detected intronic mutations in patients after MI were related to a worse clinical course and frequent occurrence of SCA. CONCLUSIONS: The novel intronic mutations may have a significant influence on the clinical course of the disease.

Detection of single nucleotide polymorphisms in coagulation factor XI deficient patients by multitemperature single-strand conformation polymorphism analysis.

Factor XI (FXI) deficiency is a rare inherited disorder which can cause bleeding complications especially in case of hemostatic challenge and/or in tissues with high fibrinolytic activity. A number of causative mutations have been described in FXI deficient individuals which have been detected by various screening methods. In this study, we present the application of the multitemperature single-strand conformation polymorphism analysis (MSSCP) on the FXI gene, a recently developed methodology for the detection of single nucleotide exchanges. We analyzed a total of 217 polymerase chain reaction (PCR) fragments from the promoter region as well as from exons 1-7 and 11-15 and compared the results to automatic fluorescent sequencing. A total of 29 PCR fragments showed single nucleotide exchanges in conventional fluorescent sequencing, representing 10 different mutations (nine missense mutations, one small deletion) and four frequent polymorphisms. With MSSCP electrophoresis at a standard temperature profile (gel temperature 35-20-10 degrees C) we were able to detect 13 of 14 (93%) different nucleotide exchanges in 25 of 29 PCR fragments (86%). Hence, the detection rate for genetic variations in the FXI gene was 86%. To evaluate the reproducibility, MSSCP was performed twice for 174 PCR fragments and the consistency between two electrophoretic runs was 99%. We conclude that the MSSCP is a sensitive, fast, and cost effective screening method for the detection of FXI gene mutations.