Bài giảng dành cho sinh viên y khoa, bác sĩ đa khoa, sau đại học. ĐH Y Dược TP Hồ Chí Minh. Etiology Pathophysiology Manifestations Diagnosis Treatment Prognosis
LONG QT SYNDROME IN CHILDREN Vu Minh Phuc MD PhD CONTENTS Etiology Pathophysiology Manifestations Diagnosis Treatment Prognosis ETIOLOGY Congenital LQTS Acquired LQTS Congenital LQTS Molecular Genotype Frequency (%) Chromosome involved Mutant Genes Defective Ionic Chanel Romano-Ward Syndrome (Autosomal Dominant) – with Normal Hearing LQT1 42 11p15.5 KCNQ1/KVLQT1 Potassium channel (IKs) LQT2 45 7q35-36 KCNH2/HERG Potassium channel (IKr) LQT3 3p21-24 SCN5A Sodium channel (INa) LQT4 ? 4q25-27 AKNB Na/Ca exchanger (INa-Ca) LQT5 21q22.2-22.2 KCNE1/mink Potassium channel (IKs) LQT6 21q22.2-22.2 KCNE2/MiRP1 Potassium channel (IKs) Jervel and Lange-Nielsen Syndrome (Autosomal Recessive) – with Deafness JLN1 JLN2 80 20 11p15.5 21q22.1-22.2 KCNQ1/KVLQT1 KCNE1/mink Potassium channel (IKs) Potassium channel (IKs) Andersen-Tawil Syndrome (Autosomal Dominant) ATS1 50 17q23 KCNJ2 Inward rectifer potassium channel (IK1) CACNA1C Cardiac L-type calcium channel (Ica.L) Timothy Syndrome (Sporadic) TS1 ? 1q42-q43 Acquired LQTS DRUGS Antibiotics : erythromycin, clarithromycin, telithromycin, azithromycin, trimethoprime- sulfamethoxazol Antifungul agents : fluconazole, itraconazole, ketoconazole Antiprotozoalagents : pentamidineisethionate Antihistamine : astemizole, terfenadine Antidepressants : tricyclics: imipramine (Tofranil), amitryptyline (Elavil), desipramine (Norpramin), and doxepin (Sinequan) Antipsychotics : haloperidol, risperidone, phenothiazine (Mellaril) and chlorpromazine (Thorazine) Antiarrhythmic agents Class 1A (sodium channel blockers) : quinidine, procainamide, disopyramide Class III (prolong depolarization) : amiodarone (rare), bretylium, dofetilide, Nacetyl procainamide, sotalol Lipid-lowering agents : probucol Antianginals : bepridil Diuretics (through K loss) : furosemide (Lasix), ethacrynic acid (Edercrin) Oral hypoglycemic agents : glibenamide, glyburide Organophosphate insecticides Promotility agents : cisapride Vasodilators : prenylamine Acquired LQTS ELECTROLYTE DISTURBANCES Hypokalemia : diuretics Hyperventilation Hypocalcemia Hypomagnesemia UNDERLYING MEDICAL CONDITION Bradycardia : complete AV block, severe bradycardia, sick sinus syndrome Myocardial function : anthracycline cardiotoxicity, congestive heart failure, myocarditis, cardiac tumors Endocrinopathy : hyperparathyroidism, hypothyroidism, pheochromocytoma Neurologic : encephalitis, head trauma, stroke, subarachnoid hemorrhage Nutritional : alcoholism, anorexia nervosa, starvation PATHOPHYSIOLOGY Na+ - Ca++ exchange Ca++ Depolarization Na+ >>> Na+ - 90 mV K+ >>> K+ Na+ - K+ ATPase exchange pump Na+ Flow of K+ down its concentration gradient MAINTENANCE OF RMP Gene Mutations Changes of channel protein structure Alteration in channel function, in permeability and selectivity Potassium channel Sodium channel Reduction in K+ channel numbers Decreased outward K+ current Intermittent reopening of multiple Na+ channels Inhibition of channel closure Abnormal inward K+ current Continued and sustained inward Na+ current Prolonged action potential Prolonged QT interval Ventricular Arrhythmias PATHOPHYSIOLOGY QT interval on ECG : duration of activation and recovery of the ventricular myocardium Prolonged recovery from electrical excitation → An increased likelihood of dispersion of refractoriness → Some parts of myocardium might be refractory to subsequent depolarization → The wave of excitation appears → Circus reentry rhythm → Ventricular tachycardia Arrhythmogenesis ─ Adrenergic stimuli : exercise, emotion, loud noise, swimming Cathecholamines enhance EADs (early afterdepolarizations) in LQTS ─ Without preceding conditions MANIFESTATIONS Invasive electrophysiologic study is not useful and unnecessary in diagnosis and prognosis of LQTS Echocardiography usually shows structurally and functionally normal heart Genetic study is only done in research MANIFESTATIONS LQTS in neonates Prolonged QT interval in neonates may be transient or may be an early indicator of LQTS It is difficult to know whether prolonged QT interval represents transient sympathetic imbalance or electrical instability that may occur in the first year of life and then disappear How to manage the patient with the previous symptoms and a prolonged QT interval who complete normalizes by year of age DIAGNOSIS Diagnostic strategy Apply for any child who has QTc = 0.46sec or a compelling borderline QTc interval with symptoms, family history, unusual T waves steps Carefully examine history: presyncope, syncope, seizure, palpitation, family history Find the causes of acquired LQTS ECG for patient and family members ─ ─ ─ QTc interval QT dispersion T waves morphology Calculate the LQTS score Conclusion and deceision DIAGNOSIS Schwartz Diagnostic Criteria for LQTS Points ECG findings QTc > 0.47 sec QTc = 0.46 - 0.47 sec QTc = 0.45 sec (male) Torsade de pointes T-wave alternans Notched T waves (3 leads) Low heart rate for age 2 1 0.5 Clinical History Syncope with stress Syncope without stress Cogenital deaness 0.5 Family History Definite LQTS Unexplained sudden death in immediate family members, age < 30 years old 0.5 DIAGNOSIS Conclusion Score ≤ Score = - Score ≥ Abnormal exercise test : exclude LQTS : possible LQTS : LQTS : LQTS Risk factors for sudden death Bradycardia for age (sinus bradycardia, junctional escape rhythm, second degree AV block) QTc interval > 0.55 sec Symptoms at presentation (syncope, seizure, cardiac arrest) Young age at presentation (< month), and Documented torsades de pointes or ventricular fibrillation T-wave alternation (major changes in T-wave morphology): relative risk factor Noncompliance with medication: important risk factor for sudden death DIAGNOSIS For bordeline cases Holter monitoring Exercise testing Epinephrine test Infusion of epinephrine at escalating doses 0.025 - 0.3 µg/ kg/ Continuous ECG monitoring during infusion QTc is prolonged in all patients with LQT subgroups TREATMENT General measures Patients and family should be aware of LQTS Medications can cause LQTS Physicians should discontinue and avoid prescribing QT prolonging medications (obligated) Cathecholamine and sympathominetic drugs No competitive sports policy applies, especially swimming Patients and family should be educated about the importance of being compliant with their medication because of sudden death TREATMENT Acquired LQTS Treatment the causes Acute treatment of arrhythmias : IV magnesium Correction of hypokalemia hypomagnesemia TREATMENT Congenital LQTS Antiarrhythmic Drugs Classes Class Channel Effects Repolarization time Drugs IA Sodium block : ++ Prolongs Quinidine, Disopyramide, Procainamide IB Sodium block : + Shortens Lidocaine, Phenytoin, Mexiletine, Tocainide IC Sodium block : +++ Unchanged Flecainide, Propafenone II If, a pacemaker and depolarizing current; indirect Ca++ channel block Unchanged Beta blockers III Repolarizing K+ currents Markedly prolongs Amiodarone, Sotalol, Ibutilide, Dofetilide IV AV nodal Ca++ block Unchanged Verapamil, Diltiazem IV-like K+ channel opener (hyperpolarization) Unchanged Adenosine TREATMENT Congenital LQTS Definite treatment when: LQTS score ≥ regardless of symptoms LQTS score = 2-3, no symptoms, associated with ─ ─ ─ ─ ─ Newborns and infants Sensorineuronal hearing loss Affected siblings with LQTS and sudden cardiac death QTc > 0.60sec or T-wave alternans Purpose to prevent the family’s or patient’s anxiety Beta blockers All beta blockers have similar effectiveness Moderate dose is better than large dose Large dose can cause bradycardia which is the high risk of sudden death Can be combined with Mexiletine in LQT3 TREATMENT Congenital LQTS Cardiac pacemaker When symptomatic bradycardia related beta- blockers Use continuous ventricular or dual chamber pacing With pacemaker, beta-blockers’ dose can be maximally used Implantable cardioverter-defibrillator (ICD) Incidence : high risk patients ICD + beta-blockers Complications: ─ ─ ─ ─ ─ Infection Lead fracture and dislodgement Inappropriate discharge Psychiatric sequelae Electrical storm TREATMENT Congenital LQTS Left cardiac sympathetic denervation Remove the lower part of the stellate ganglion and first thoracic ganglia: no risk for Homer’s syndrome Left cervicothoracic sympathectomy: ─ Provides inadequate cardiac sympathetic denervation ─ Homer’s syndrome Other treatment Potassium supplementation in LQT2 and/or Spironolactone For acute arrhythmias: VT, torsade de pointes PROGNOSIS LQTS is a serious disease, treatment is only partially effective Untreated patients : prognosis is very poor : 20% : 50% With beta-blockers Annual mortality 10-year mortality Cardiac events : 30% 80% of deaths occur while patients are taking beta-blockers With cardiac pacemaker : 16% have cardiac events With ICD : prognosis appears better With left cardiac sympathetic denervation Sudden death 5-year survival rate : 8% : 94% Thanks for your attention ... LQT1 42 11p15.5 KCNQ1/KVLQT1 Potassium channel (IKs) LQT2 45 7q35-36 KCNH2/HERG Potassium channel (IKr) LQT3 3p21-24 SCN5A Sodium channel (INa) LQT4 ? 4q25-27 AKNB Na/Ca exchanger (INa-Ca) LQT5... isolation in diagnosis LQTS Large, notched T waves (“hump”) or T-wave alternans are suspicious for LQTS, even with normal QTc - LQT1 : broad-based, prolonged T waves (IKs) - LQT2 : low-amplitude,... spells Romano-Ward (LQT1- LQT6) Family history of LQTS : ±, (-) > (+) Normal hearing, syncope Cardiac events occur during ─ stress or exercise in LQT2 ─ rest or sleep in LQT3 when the HR is