Sudden Cardiac Death in Structurally Normal Heart Brian D. Le, MD Presbyterian Hospital CIVA

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

A- 35 yo WM c syncope B- 31 yo sister, dizziness and palpitations C- 6 yo son, SCD

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.” 300-400,000 deaths annually (U.S.). VT/VF account for 80%. 20% have structurally normal hearts. Wever E, et al. JACC. Vol 43, 2004.

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.

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 (600-800ms). Short-coupled TdP: normal QTc, PVC w/short coupling (200-300ms). 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.

Brugada’s

Catecholaminergic Polymorphic VT

Idiopathic VF

A- 35 yo WM c syncope B- 31 yo sister, dizziness and palpitations C- 6 yo son, SCD

Evaluation Physical Exam Serial ECG’s Holter Heart rate variability QT dispersion Signal-averaged ECG Echocardiogram Cardiac MRI Electrophysiological Study

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).

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.

Familial Short QT Gussak et al. Cardiology 2000;94:99-102. 3 members of one family; age 17-51 yo. Palpitations, sx PAF, syncopeSCD All w/ structurally normal hearts. All w/ S-QT (260-280ms); QT interval <80% predicted by Rautaharju method.

Factors That Shorten QT Increase in heart rate Hyperthermia Hypercalcemia Hyperkalemia Acidosis Changes in autonomic tone

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

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 leadsLQT1 Bellocq et al. Circulation. 109; 2004

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. 2005; 96

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

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.

Short QT Rx Results Flecainide: slight inc. QT due to QRS prolongation. Ibutilide & Sotalol: no change in QT Hydroquinidine: 5/6 pts- QTc normalized (290405ms) 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.

Ventricular ERP

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.

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.

ICD First line therapy Risk of inappropriate shock delivery- Tw oversensing (Schimpf et al. JCE. 14: Dec 2003)

- Ventricular ERP- <150ms - induction of VF - Atrial ERP- 120ms Circulation. 2003; 108

Family Tree 49 yo 39 yo 39 yo 8 mo Circulation. 2003; 108

Schimpf, et al. Heart Rhythm. 2004;2

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.