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Sudden Cardiac Death in Structurally Normal Heart
Brian D. Le, MD Presbyterian Hospital CIVA
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Gaita et al. Circulation. 2003; 108
Presentation HPI-35 yo WM s PMH presents with exertional syncope h/o PAF since 18 yrs of age Holter- monomorphic isolated PVC’s Echo- structurally normal heart Meds- no OTC or herbal Social- occ. Etoh, no IVDA Family History Sister (31) - dizziness and palpitations Sister’s son (6) - cardiac arrest at 8 mo old after a loud noise with successful DCCV Gaita et al. Circulation. 2003; 108
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A- 35 yo WM c syncope B- 31 yo sister, dizziness and palpitations C- 6 yo son, SCD
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Sudden Cardiac Death “Unexpected death from cardiac cause within a short time (~1 hour of sx) in a person without prior conditions that would appear fatal.” ,000 deaths annually (U.S.). VT/VF account for 80%. 20% have structurally normal hearts. Wever E, et al. JACC. Vol 43, 2004.
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Sudden Cardiac Death Normal hearts, < 40 years old
< 30% successful resuscitation reaching hospital Risk of life-threatening events in cardiac arrest survivors is 25-40% at two years Wever E, et al. JACC. Vol 43, 2004.
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Primary Electrophysiologic Abnormalities
WPW: anterograde BPT ERP <250ms. Brugada: RBBB w/ST elevation V1-V3 Catecholamine Polymorphic VT: hRyR2. Long QT: QTc (>440ms), TdP w/long coupled PVC ( ms). Short-coupled TdP: normal QTc, PVC w/short coupling ( ms). Short QT syndrome Idiopathic VF LQT1: KVLQT1; LQT2: HERG (KCNH2); LQT3: SNC5A; LQT4:?; LQT5/6: KCNE1 & KCNE2; LQT7:?. Romano Ward: Auto Dominant LQTS Jervel-Lange-Neilsen: Auto Recessive LQTS + deafness.
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Brugada’s
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Catecholaminergic Polymorphic VT
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Idiopathic VF
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A- 35 yo WM c syncope B- 31 yo sister, dizziness and palpitations C- 6 yo son, SCD
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Evaluation Physical Exam Serial ECG’s Holter Heart rate variability
QT dispersion Signal-averaged ECG Echocardiogram Cardiac MRI Electrophysiological Study
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QT Interval Represents ventricular repolarization.
Normal QTc upper limit: 440ms. Bazett’s formula: QTc = QT/ RR Rautaharju formula (14,379 pts): QTp (ms)= 656/ (1+HR/100) QT/QTp x 100% = % QTpredicted. 88% of QTp = 2 SD below mean Lower limit of nl QT int. = 88% of QTp Rautaharju: <88% QTp (2.5% of patients studied); <80% QTp (0.03% of patients studied).
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QT Interval and SCD Algra et al. Br.Ht.J. 1993;70:43-8.
Nested cohort 6693 consecutive pts w/24 ECG. F/U 2.5 years in 99.5% of pts. End point: QTc correlation w/SCD (104 pts). Results: QTc >= 440ms 2.3 RR of SCD. QTc < 400ms 2.4 RR of SCD.
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Familial Short QT Gussak et al. Cardiology 2000;94:99-102.
3 members of one family; age yo. Palpitations, sx PAF, syncopeSCD All w/ structurally normal hearts. All w/ S-QT ( ms); QT interval <80% predicted by Rautaharju method.
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Factors That Shorten QT
Increase in heart rate Hyperthermia Hypercalcemia Hyperkalemia Acidosis Changes in autonomic tone
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Genetic Basis of Short QT
Brugada, Antzelevitch, et al. Circ. 2004;109:30-5. Different missense mutations in same residue codon 588 of KCNH2 (HERG [IKr]). Mutations only seen in sQT, and not in normal relatives. Patch clamp models Screened: HERG (KCNH2), KCNE2, KCNQ1, KCNE1, SCN5A, KCNJ2, Kv4.3, Kv4.2,Kv1.5, KCHiP2, KCHAP, KCHiP1, KCNJ3, KCNJ6, SUR1, KCNJ11, ANKB, CHRM1,4,&5. N=asparagine 588=codon # K=Lysine
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Heterogeneity of Short QT
Genetic Studies- KCNQ1 gene mutation G for C, subs. valine for leucine (IKs) Mutations negative in 200 unrelated controlled individuals Loss of function leadsLQT1 Bellocq et al. Circulation. 109; 2004
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KCNJ2, encoding for inwardly rectifying K channel Kir2.1
Rapid repolarization SQT3 Loss of function results in LQT7 (Anderson’s disease) Priori et al. Circ. Res ; 96
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Ion Channel Mutations Loss of Function Gain of Function
SCN5A Brugada IKs LQT1 IKr LQT2 Gain of Function SCN5A LQT3 IKs Fam. A. Fib., Short QT IKr Short QT 4 1 2 3 Na Ca > Na IKr & IKs
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Short QT Syndrome Rx Gaita et al. JACC. 2004;43:1494-9.
6 pts. from 2 different families. Drugs: Flecainide (IV or oral), Sotalol, Ibutilide, and Hydroquinidine. Steady-state: >5 t1/2 of drug. Flecainide (Class 1c)dose: IV 2mg/kg in 10 mins; oral 100mg po BID. Sotalol (class 3): IV 50mg and oral til max tolerated (which was 80mg po BID). Ibutilide (class 3): 1mg IV in 10mins. Hydroquinidine (class 1a): 250mg po TID or 500mg po BID.
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Short QT Rx Results Flecainide: slight inc. QT due to QRS prolongation. Ibutilide & Sotalol: no change in QT Hydroquinidine: 5/6 pts- QTc normalized (290405ms) EPS 5/5 pts- inc. VERP, no VF/VT F/U 11 mos- 4/6 on hydroquinidine w/o sx or arrhythmias detected by ICD.
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Ventricular ERP
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Figure 1. Twelve-lead electrocardiographic (ECG) recordings of Patient 1, while treated with different antiarrhythmic drugs. From left to right: basal ECG; during oral flecainide administration, oral sotalol, ibutilide, and hydroquinidine. During hydroquinidine administration: QT prolongation and ST-T changes: appearance of ST-segment, T-wave increases in duration.
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Quinidine VW Class: Ia (sodium channel blocker)
Blocks: INa, IKr, IKs, Ito, L-type Ca2+, IK1(in.rect.), & IKATP QT increase. Adverse effects: diarrhea, SLE, thrombocytopenia, hepatitis, cinchonism (tinnitus/HA), TdP, many drug interactions 2/2 block of CYP2D6.
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ICD First line therapy Risk of inappropriate shock delivery- Tw oversensing (Schimpf et al. JCE. 14: Dec 2003)
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- Ventricular ERP- <150ms - induction of VF - Atrial ERP- 120ms
Circulation. 2003; 108
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Family Tree 49 yo 39 yo 39 yo 8 mo Circulation. 2003; 108
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Schimpf, et al. Heart Rhythm. 2004;2
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Summary Short QT Syndrome
Significantly short QTc <= 300ms. Tall & peaked T-waves. Clinical: palpitations, syncope, SCD. Significant FHX of SCD. Atrial and ventricular arrhythmias. Structurally normal hearts. Treatment: ICD and/or Quinidine.
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