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

2. 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

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

4. 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.

5. 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.

6. 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.

7. Brugada’s

8. Catecholaminergic Polymorphic VT

9. Idiopathic VF

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

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

12. 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).

13. 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.

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

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

16. 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

17. 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

18. 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

19. 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

20. 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.

21. 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.

22. Ventricular ERP

23. 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.

24. 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.

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

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

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

28. Schimpf, et al. Heart Rhythm. 2004;2

29. 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.