Sudden Cardiac Death in Structurally Normal Heart

Brian D. Le, MD Presbyterian Hospital CIVA

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

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

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

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 – SCN5A  – IKs  Brugada LQT1 – IKr  LQT2 1 Na 0  2 Gain of Function – SCN5A  – IKs  LQT3 Fam. A. Fib., Short QT – IKr  Short QT Ca > Na IKr & IKs 3 4

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.

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

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.