Wojciech Szczepański, MD, PhD Department of Pediatrics, Endocrinology, Diabetology with Cardiology Division Medical University of Bialystok

Transcription

1 Channelopathies: - Long QT syndrome - Short QT syndrome - Brugada syndrome - Early repolarization syndrome - Catecholaminergic polymorphic ventricular tachycardia Wojciech Szczepański, MD, PhD Department of Pediatrics, Endocrinology, Diabetology with Cardiology Division Medical University of Bialystok

2 Basics QTc = QT/ RR seconds

3 Long QT syndrome (LQTs) The long QT syndrome (LQTS) is the phenotypic description of a group of disorders characterized by a prolonged QT interval in association with a characteristic arrhythmia, polymorphic ventricular tachycardia

4 History 1856 r. Meissner described a case of a deaf girl, who died after her teacher yelled at her, a couple years back her deaf brother also died after being terribly scared; 1957 r. first documented by ECG case of long QT syndrome with deafness, inherited in autosomal recessive pattern (Jerwell, Lange- Nielsen syndrome); 1963 r. long QT syndrome with normal hearing, inherited in autosomal dominant pattern (Romano-Ward syndrome); before 1993 r. increased sympathetic tone on the left, decreased on the right.

5 Aetiology Defective ion channel proteins in the basement membrane of heart muscle cells; Apoptosis of cells in the nodes of the conduction system of the heart (not well-proven) Acquired (medication, metabolic abnormalities)

6 Aetiology

7 Aetiology Healthy LQTs

8 Aetiology LQTs type Mutation Gene Channel LQT1 11p15.5 KVLQT1, or KCNQ1 (heterozygote) Potassium (I Ks ) LQT2 7q35-36 HERG, KCNH2 Potassium (I Kr ) LQT3 3p21-24 SCN5A Sodium (I Na ) LQT4 4q25-27 ANK2, ANKB LQT5 21q KCNE1 (heterozygote) Sodium, potasium, calcium Potassium (I Ks ) LQT6 21q MiRP1, KNCE2 Potassium (I Kr ) LQT7 (Anderson syndrome) Romano-Ward syndrome (AD) 17q23.1-q24.2 KCNJ2 Potassium (I K1 )

9 Aetiology LQTs type Mutation Gene Channel LQT8 (Timothy syndrome) 12q13.3 CACNA1C Calcium (I Ca-Lalpha ) LQT9 3p25.3 CAV3 Sodium (I Na ) LQT10 11q23.3 SCN4B Sodium (I Na ) LQT11 7q21-q22 AKAP9 Potassium (I Ks ) LQT12 20q11.2 SNTAI Sodium (I Na ) JLN1* 11p15.5 JLN2* 21q *JLN - Jerwell, Lange-Nielsen syndrome (AR) KVLQT1 lub KCNQ1 (homozygote) KCNE1 (homozygote) Potassium (I Ks ) Potassium (I Ks )

10 Aetiology < 1% < 1% 35% 10% 35%

11 Epidemiology 1 : no racial differences; 85% hereditary; 60 70% of cases are diagnosed in women; mortality rate is at about 6% before the age of 40 (more common in boys and young men ); 10 15% of patients with mutations in genes don t have LQTs; 2,5% of healthy population has LQTs (???)

12 Symptoms = 10% No symptoms Heart palpitations Syncope Syncope and convulsions Sudden death

13 Diagnostics ECG Prolongation of QT (II or V5) corrected according to Bazet formula (50-120/min; tachycardia overestimation, bradycardia underestimation); QTc ECG Propability of LQTS QTc > 460 ms Prolonged QT 95 % 460 ms > QTc > 420 ms Borderline QT 5 % QTc < 420 ms Normal QT < 1 % ad children < 15 y.a. 450 ms ( ms borderline) > 460 ms ( ms borderline)

14 = 0,46/0,9 = 0,51 s RR QT

15 Diagnostics ECG Differences in the shape of T wave: LQTS1 short ST, wide T; LQTS2 normal ST, low and two-humped T; LQTS3 long ST, narrow and pointed T; LQT7 large U wave; Bradycardia; Lack of HR acceleration during exercise; II atrio-ventricular block 2 : 1.

16 Diagnostics criteria Schwartz i Moss criteria 4 pts high probability 2-3 pts intermediate probability 0,5-1 pts low probability ECG Clinical Family Symptom Punkty QTc 480 ms 3 QTc ms 2 QTc 450 ms (males) 2 Torsade de pointes 2 T wave liability 1 Notched T wave in at least 3 leads 1 Bradycardia 0,5 Syncope preceded by stress 2 Syncope without any stressful situation 1 Congenital deafness 0,5 Member of family with LQTs 1 Sudden death in family < 30 y.a. 0,5

17 Diagnostics other 24-hour ECG Holter monitoring: - QT changes inadequate to HR liability; - inadequate HR changes; - bradycardia (30%); Exercise test: - changing QTc as a response to exercise (assessment of QTc in the 1 or 2 minute after the exercise test); - tachycardia; Invasive electrophysiological diagnostics; Genetic tests;

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19 Consequences VT Ventricular fibrillation Torsade de pointes

20 Factors favouring the arrhythmia Long QT (prolongation by 10 ms increases the risk by 5%); Bradycardia (twice the risk); Specific type of LQTs (LQT3, 12 months after pregnancy LQT2); Syncope or cardiac arrest in last 2 years; medical noncompliance after an event Sympathetic stimulation: - exercise (swimming); - loud noises (phone, doorbell); - emotions (stress);

21 Drug-induced QT prolongation epinephrine antihistamina - difenhydramine - terfenadine - astemizol antibiotics - erythromycin - trimethoprim with sulfametoxazole antiarytmicum - sotalol gastrological - cisaprid psychotropic agents antifungal - ketokonozol - flukonazol - itrakonazol

22 Factors favouring drug-induced LQTc Being a female; Hypokalemia; Hypocalcaemia; Pheochromocytoma; Hypothermia; Thyroid gland diseases;

23 Treatment Potassium and magnesium suplementation; Beta blockers: - Propranolol (2-3 mg/kg b.w./24 h); - Nadolol ( mg/24 h); - Metoprolol - Atenolol Implantable cardioverter-defibrillator: - QTc > 500 ms; - heart arrest, recurrent syncopes, torsade de pointes while on beta blockers;

24 Management No physical exercise; No loud noises; No stress; Avoiding specific medicine; ECG in family members (observe males with QTc > 430 ms and females with QTc > 437 ms); Education of family members in CPR;

25 Short QT syndrome (SQTs) Short QT Syndrome (SQTS) is an inherited channelopathy associated with marked shortened QT intervals and sudden cardiac death in individuals with a structurally normal heart

26 History 1996 r. first notice; 2000 r. first publication; 2003 r. first implantable cardioverter-defibrillator treatment; 2004 r. first drug-effectiveness studies; 2004 r. first genetic discoveries;

27 Aetiology Increased activity of a centrifugal potassium current activity I KR and inharmonious repolarisation of atria and ventricles SQT1 KCNH2 SQT2 KCNQ1 SQT3 KCNJ2

28 Epidemiology Over a houndred cases; Inherited in autosomal dominant pattern; High mortality;

29 Symptoms Dizziness; Syncope; Sudden death; Atrial fibrillation (especially in younger age)

30 Diagnosis QTc: < 300 ms high probability (in some studies < 320 ms or < 360 ms); High, pointed T wave; No QTc changes with HR variablity; Genetics Secondary causes of short QT interval such as hyperkalemia, acidosis, hypercalcemia, hyperthermia, effect of drugs like digitalis

31 Treatment Implantable cardioverter-defibrillator Quinidin, disopyramide, amiodarone

32 Brugada syndrome Patients with typical ECG features who are asymptomatic and have no other clinical criteria are said to have the Brugada pattern. Patients with typical ECG features who have experienced sudden cardiac death or a sustained ventricular tachyarrhythmia, or who have one or more of the other associated clinical criteria, are said to have the Brugada syndrome

33 History 1980 r. CDC reported many cases of deaths in immigrants from Asia (Tailand, Philipines, Japan). In Asia sudden death in young males is a problem known for ages r. report about an ECG of a polish 3-year-old who was resuscitated many times because of sudden cardiac arrests, his sister died at the age of 2 and she was also resuscitated many times r. 8 cases described by Brugadas, atrial fibrillation is the cause of death in patients with a characteristic ECG pattern.

34 Aetiology Genetically determined, most often defective sodium channel with early deactivation of sodium current I Na. SCN5A

35 Epidemiology Frequency isn t well established; in Western Europe it is estimated at 1 : people and in Japan at 1 : 1500 people. Inherited in autosomal dominant pattern. It is estimated to be responsible for approximately 4% of sudden deaths and 20% of sudden deaths in people with structurally normal heart, Lai Tai mortality in Thailand is estimated for 30 : More common in Asian population times more common in males but both genders have exual probability of gene mutation. Median age of first symptoms is between 30th and 50th birthday, median age of sudden death is 41.

36 Symptoms Syncope; Sudden death (while asleep) or cardiac arrest; Ventricular fibrillation persistent ventricular tachycardia;

37 Diagnosis Type 1 Type 2 Type 2 J-point 2 mm 2 mm 2 mm T wave Negative Lai Tai Positive or biphasic Positive ST-T Coved type Saddle back Saddle back ST Decreasing Elevation 1 mm Elevation 0,5-1 mm

38 Diagnosis ECG pattern + at least one of the following: Documented ventricular fibrillation Polymorphic ventricular tachycardia (VT) Family history of sudden cardiac death at less than 45 years of age Family history of type 1 Brugada pattern ECG changes Inducible VT during electrophysiology study Unexplained syncope suggestive of a tachyarrhythmia Nocturnal agonal respiration

39 Diagnosis Genetic testing Pharmacological tests flecainid 2 mg/kg (max 150 mg) for 10 minut, prokainamid 10 mg/kg for 10 minutes, ajmalin 1 mg/kg for 5 minutes test should be stopped when characteristic ECG pattern (ST elevation in V1/V2/V3 1 mm at the distance of 0,08 s from J-point), ventricular tachycardia or QT prolongation of at least 30% appear. Electrophysiological testing (checking for the risk of arrhythmia). Differential diagnostics with hyperkalcemia and hyperkalemia. Differential diagnostics with arrhythmogenic cardiomyopathy of the right ventricle and hypertrophic cardiomyopathy.

40 Risk factors of arrhythmia Sodium channel blockers, fever, vagotonic agents, alfa-adrenergic agonists, beta-adrenolitics, tricyclic antidepressants, I generation antihistaminic agents, cocaine. After bringing back to life after cardiac arrest the risk of recurrent is estimated to be 69% With recurrent syncopes or characteristic ECG pattern the risk of sudden death is estimated to be 19% In asymptomatic patients the risk of sudden death is estimated to be 8%.

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42 Treatment Patients with only the Brugada ECG pattern and with no family history of sudden death do not require any specific therapy Quinidin (???);

43 Early repolarization syndrom (ERS) The ER pattern describes the patient with appropriate ECG findings in the absence of symptomatic arrhythmias. The ER syndrome applies to the patient with both appropriate ECG findings and symptomatic arrhythmias.

44 Aetiology KCNJ8 gene (responsible for the ATP sensitive potassium channel Kir6.1 - I KATP current); CACNA1C, CACNB2, CACNA2D1 genes (responsible for the cardiac L- type calcium channel - I Ca.L current); SCN5A gene (responsible for the sodium channel - I Na current)

45 Epidemiology ECG pattern occurs in 5-13% of general population Usually in young people, males, athletes It might be related to higher risk of sudden cardiac death

46 Diagnosis The presence of slurring at the terminal part of the QRS complex A sharp well-defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST segment. J-point elevation of 0.1 mv in two adjacent leads with either a slurred or notched morphology

47 Diagnosis Expert consensus statement on diagnosis 1. ER syndrome is diagnosed in the presence of J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG in a patient resuscitated from otherwise unexplained VF/polymorphic VT. 2. ER syndrome can be diagnosed in an SCD victim with a negative autopsy and medical chart review with a previous ECG demonstrating J- point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG. 3. ER pattern can be diagnosed in the presence of J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG.

48 Diagnosis

49 Treatment CLASS I 1. ICD implantation is recommended in patients with a diagnosis of ER syndrome who have survived a cardiac arrest. CLASS IIa 2. Isoproterenol infusion can be useful in suppressing electrical storms in patients with a diagnosis of ER syndrome. 3. Quinidine in addition to an ICD can be useful for secondary prevention of VF in patients with a diagnosis of ER syndrome. CLASS IIb 4. ICD implantation may be considered in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST-segment elevation >1 mm in 2 inferior or lateral leads. 5. ICD implantation may be considered in asymptomatic individuals who demonstrate a highrisk ER ECG pattern (high J-wave amplitude, horizontal/descending ST segment) in the presence of a strong family history of juvenile unexplained sudden death with or without a pathogenic mutation. CLASS III 6. ICD implantation is not recommended in asymptomatic patients with an isolated ER ECG pattern.

50 Catecholaminergic polymorphic ventricular tachycardia

51 Definition/diagnosis A ventricular rhythm at a rate greater than 100 beats per minute in the absence of structural heart disease or known associated syndromes with: Typical polymorphic VT with continuously varying QRS morphology, similar to that seen in patients with acute ischemia or non-ischemic cardiomyopathies OR Bidirectional tachycardia demonstrating alternans of the QRS complexes

52 Aetiology The cardiac ryanodine receptor gene and the calsequestrin 2 gene. Both mutations appear to act by inducing diastolic calcium release from the sarcoplasmic reticulum. The resulting intracellular calcium overload leads to delayed afterdepolarizations and triggered activity, which can induce ventricular tachycardia and fibrillation.

53 Treatment Avoiding competitive sports. Use of beta blockers for all adult patients with spontaneous or documented stressinduced ventricular arrhythmias For survivors of cardiac arrest or for patients with syncope or sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) despite therapy with beta blockers, placement of an implantable cardioverter-defibrillator is recommended In patients taking a beta blocker who have received an ICD and who continue to have stress-induced ventricular arrhythmias the addition of flecainide for further arrhythmia suppression is recommended. Verapamil may also be considered. Left sympathetic denervation for patients with CPVT who remain symptomatic after maximal medical therapy. Use of beta blockers in patients without clinical manifestations who are diagnosed in childhood based upon genetic analysis.