Gregor%20Mendel J. G. Mendel Vfib Sudden cardiac death (USA 400.000 deaths/year) Paris prospective study >7000 males followed cca 23 years Multivariant analysis of relative risk of sudden cardiac death (SCD) RR P BMI 1,21 0,03 Smoking 1,34 0,0001 Diabetes 2,21 0,02 Heart rate 1,22 0,007 Systolic BP 1,23 0,02 Cholesterol 1,23 0,0001 Fam. history of MI 1,16 - Family history of SCD - in one parent 1,8 0,01 - in both parents 9,4 • Being aware of external risk factors shared in a particular family it is obvious that genetically determined variations of physiological proceses must exist that increase the risk of SCD. •In these cases mutations of single genes does not play crucial role. Etiology is much more complicated. Familial occurence of SCD in common population Pathophysiology of SCD on molecular level 2) processes and factors of aterosclerotic plaque stability, thrombosis and ischemia in coronary vessels 1) processes of electric impulse creation and propagation in myocardium 3) central and local control of myocardial excitablity and vascular motorics Hereditary arrhythmic diseases = a model of arrythmogenesis • prolongation of QT interval on surface ECG • syncopi or even sudden death due to polymorphic ventricular tachycardia (torsades de pointes) • structurally normal heart Congenital long QT syndrome (LQTS) fáze 0 1 2 3 4 INa ICaL ITO IKr IKs IK1 Ion channel genes a subunit b- subunit SCN5A SCN1B KCND3, KCNA4 CACNA1A CACNB1, B2 KCNH2 KCNE2 KCNQ1 KCNE1 KCNJ2, KCNJ12 LQT syndrom LQTS typ chromozom gen protein Romano - Ward sy (1:10 000) LQT 1 11p15.5 KCNQ1 (KVLQT1) a IKs LQT 2 7q35-36 KCNH2 (HERG) a IKr LQT 3 3p21-24 SCN5A a INa LQT 4 4q25-27 ANK2 ankyrin B LQT 5 21q22.1-22.2 KCNE1 minK (b IKs) LQT 6 21q22.1 KCNE2 MIRP (b IKr) (Andersen sy, Timothy sy…) Jervell - Lange-Nielsen sy (1:1,5 mln) JLN 1 11p15.5 KCNQ1 (KVLQT1) a IKs JLN 2 21q22.1-22.2 KCNE1 b IKs LQTS types - genes and proteins Circulation 2009;120:1761-1767 ECG was performed in 44 596 infants 15 to 25 days old prevalence of at least 1:2534 apparently healthy live births ECG signs: A. QTc (Bazett) > 480 ms 3 460 - 470 ms 2 450 ms in male 1 B. Torsades de pointes 2 C. T wave alternans 1 D. Notched T wave in 3 leads 1 E. Low heart rate in children 0,5 History A. Syncope with exercise 2 without exercise 1 B. Congenital deafness 0,5 Family H. A. Direct relative with dg. LQTS 1 B. Sudden death in family below age 30 0,5 Scoring: <1 point – low, 2-3 points – intermediate, >3,5 – high probability of the dg LQTS diagnostic score (Schwartz et al., 1993) EKG_LQT_DM QTc >500 ms = high risk RR QT QT interval correction to the heart rate Bazett – QT Fridericia – QT ÖRR 3Ö RR Linear relationship Square root relationship Day 0 1 7 30 Batchvarov VN, et al. Am J Physiol Heart Circ Physiol 2000;282:H2356-63. polymorphic ventricular tachycardia „torsade de pointes“ Vfib sejmout0003 Dessertenne F. Le tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur Vaiss. 1966;59:263-72. Camm AJ, Malik M, Yap YG. Acquired long QT syndrome. Blackwell Futura, 2004. ECG Blood pressure Leading symptome - syncope - during exercise, jumps in water - but also at rest, strong acoustic signals Very often seizures!!! . Torsade is an incomplete circulatory arrest causing non-coordinated muscular acitivity – seizures. TdP_polek_sur A case report 47-year old female with repeated seizures classified as status epilepticus at the Emergency Torsades de pointes 5 sec Movement artefacts = seizures WCT One normal another normal TdP_polek_sur2 Continuing ECG shows QT interval prolongation The lady had low potassium level and was on antirheumatoid drug Plaquenil (hydroxychlorochine) = drug induced long QT syndrome QT interval prolonging drugs Antiarrhythmics - ajmaline, amiodarone, bretylium, dofetilide, disopyramide, ibutilide, prokainamide, propafenone, chinidin, sotalol Antibiotics, chemotherapeutics, antimycotics - amantadine, clarytrhomycine, chloroquine, cotrimoxazole, erythromycine, fluconazole, halofantrine, itraconazole, ketoconazole, pentamidine, chinine, spiramycine, sparfloxacine Antihistaminics - astemizole, loratadine, terfenadine Psychopharmacs - amitryptiline, clomipramine, clozapine, chlorpromazine, citalopram, desipramine, doxepine, droperidol, fluoxetine, fluphenazine, haloperidol, imipramine, lithium, maprotiline, mesoridazine, nortryptiline, pericycline, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sultopride, thioridazine, timiperone, trifluoperazone, venlafaxine, zimeldine, ziprasidone Other - cisapride, indapamide, ketanserine, probucol, hydroxychlorochine, sildenafil, vasopresin www.qtdrugs.org