Sudden Cardiac Death Sudden Cardiac Death in Structurally Normal in Structurally Normal

HeartHeart

Brian D. Le, MDBrian D. Le, MD

Presbyterian HospitalPresbyterian Hospital

CIVACIVA

PresentationPresentation– HPIHPI-35 yo WM s PMH presents with -35 yo WM s PMH presents with

exertional syncopeexertional syncope h/o PAF since 18 yrs of ageh/o PAF since 18 yrs of age Holter- monomorphic isolated PVC’sHolter- monomorphic isolated PVC’s Echo- structurally normal heartEcho- structurally normal heart

– MedsMeds- no OTC or herbal- no OTC or herbal– SocialSocial- occ. Etoh, no IVDA- occ. Etoh, no IVDA– Family HistoryFamily History

Sister (31) - dizziness and palpitationsSister (31) - dizziness and palpitations Sister’s son (6) - cardiac arrest at 8 mo Sister’s son (6) - cardiac arrest at 8 mo

old after a loud noise with successful old after a loud noise with successful DCCVDCCV Gaita et al. Gaita et al. CirculationCirculation. 2003; 108. 2003; 108

A-A- 35 yo WM c 35 yo WM c syncopesyncope

B-B- 31 yo sister, 31 yo sister, dizziness and dizziness and palpitationspalpitations

C-C- 6 yo son, SCD 6 yo son, SCD

Sudden Cardiac DeathSudden Cardiac Death

““Unexpected death from cardiac cause Unexpected death from cardiac cause within a short time (~1 hour of sx) in a within a short time (~1 hour of sx) in a person without prior conditions that person without prior conditions that would appear fatal.”would appear fatal.”

300-400,000 deaths annually (U.S.).300-400,000 deaths annually (U.S.). VT/VF account for 80%.VT/VF account for 80%. 20% have structurally normal hearts.20% have structurally normal hearts.

Wever E, et al. Wever E, et al. JACCJACC. Vol 43, 2004.. Vol 43, 2004.

Sudden Cardiac DeathSudden Cardiac Death

Normal hearts, < 40 years oldNormal hearts, < 40 years old << 30% successful resuscitation 30% successful resuscitation

reaching hospitalreaching hospital Risk of life-threatening events in Risk of life-threatening events in

cardiac arrest survivors is 25-40% cardiac arrest survivors is 25-40% at two yearsat two years

Wever E, et al. Wever E, et al. JACCJACC. Vol 43, 2004.. Vol 43, 2004.

Primary Primary Electrophysiologic Electrophysiologic

AbnormalitiesAbnormalities WPWWPW: anterograde BPT ERP <250ms.: anterograde BPT ERP <250ms. BrugadaBrugada: RBBB w/ST elevation V1-V3: RBBB w/ST elevation V1-V3 Catecholamine Polymorphic VTCatecholamine Polymorphic VT:: hRyR2. hRyR2. Long QTLong QT: QTc (>440ms), TdP w/long : QTc (>440ms), TdP w/long

coupled PVC (600-800ms). coupled PVC (600-800ms). Short-coupled TdPShort-coupled TdP: normal QTc, PVC : normal QTc, PVC

w/short coupling (200-300ms).w/short coupling (200-300ms). Short QT syndromeShort QT syndrome Idiopathic VFIdiopathic VF

Brugada’sBrugada’s

Catecholaminergic Catecholaminergic Polymorphic VTPolymorphic VT

Idiopathic VFIdiopathic VF

A-A- 35 yo WM c 35 yo WM c syncopesyncope

B-B- 31 yo sister, 31 yo sister, dizziness and dizziness and palpitationspalpitations

C-C- 6 yo son, SCD 6 yo son, SCD

EvaluationEvaluation

Physical ExamPhysical Exam Serial ECG’sSerial ECG’s HolterHolter Heart rate variabilityHeart rate variability QT dispersionQT dispersion Signal-averaged ECGSignal-averaged ECG EchocardiogramEchocardiogram Cardiac MRICardiac MRI Electrophysiological StudyElectrophysiological Study

QT IntervalQT Interval

Represents ventricular Represents ventricular repolarization.repolarization.

Normal QTc upper limit: 440ms.Normal QTc upper limit: 440ms. Bazett’s formula: QTc = QT/ RRBazett’s formula: QTc = QT/ RR Rautaharju formula (14,379 pts):Rautaharju formula (14,379 pts):

– QTp (ms)= 656/ (1+HR/100)QTp (ms)= 656/ (1+HR/100)– QT/QTp x 100% = % QTpredicted.QT/QTp x 100% = % QTpredicted.– 88% of QTp = 2 SD below mean88% of QTp = 2 SD below mean– Lower limit of nl QT int. = 88% of QTpLower limit of nl QT int. = 88% of QTp

QT Interval and SCDQT Interval and SCD

Algra et al. Br.Ht.J. 1993;70:43-8.Algra et al. Br.Ht.J. 1993;70:43-8.– Nested cohort 6693 consecutive pts Nested cohort 6693 consecutive pts

w/24 ECG.w/24 ECG.– F/U 2.5 years in 99.5% of pts.F/U 2.5 years in 99.5% of pts.– End point: QTc correlation w/SCD End point: QTc correlation w/SCD

(104 pts).(104 pts).– Results:Results:

QTc >= 440ms QTc >= 440ms 2.3 RR of SCD. 2.3 RR of SCD. QTc < 400ms QTc < 400ms 2.4 RR of SCD. 2.4 RR of SCD.

Familial Short QTFamilial Short QT

Gussak et al. Cardiology Gussak et al. Cardiology 2000;94:99-102.2000;94:99-102.– 3 members of one family; age 17-51 3 members of one family; age 17-51

yo.yo.– Palpitations, sx PAF, syncopePalpitations, sx PAF, syncopeSCDSCD– All w/ structurally normal hearts.All w/ structurally normal hearts.– All w/ S-QT (260-280ms); QT interval All w/ S-QT (260-280ms); QT interval

<80% predicted by Rautaharju <80% predicted by Rautaharju method.method.

Factors That Shorten Factors That Shorten QTQT Increase in heart rateIncrease in heart rate HyperthermiaHyperthermia HypercalcemiaHypercalcemia HyperkalemiaHyperkalemia AcidosisAcidosis Changes in autonomic toneChanges in autonomic tone

Genetic Basis of Short Genetic Basis of Short QTQT Brugada, Antzelevitch, et al. Circ. Brugada, Antzelevitch, et al. Circ.

2004;109:30-5.2004;109:30-5.– Different missense mutations in same Different missense mutations in same

residue codon 588 of KCNH2 (HERG residue codon 588 of KCNH2 (HERG [IKr]).[IKr]).

– Mutations only seen in sQT, and not in Mutations only seen in sQT, and not in normal relatives.normal relatives.

– Patch clamp modelsPatch clamp models

Heterogeneity of Short Heterogeneity of Short QTQT

Genetic Studies- KCNQ1 gene Genetic Studies- KCNQ1 gene mutation G for C, subs. valine for mutation G for C, subs. valine for leucine (IKs)leucine (IKs)

Mutations negative in 200 Mutations negative in 200 unrelated controlled individualsunrelated controlled individuals

Loss of function leadsLoss of function leadsLQT1LQT1

Bellocq et al. Bellocq et al. Circulation. Circulation. 109; 109; 20042004

KCNJ2, encoding for inwardly KCNJ2, encoding for inwardly rectifying K channel Kir2.1rectifying K channel Kir2.1

Rapid repolarizationRapid repolarization SQT3SQT3 Loss of function results in LQT7 Loss of function results in LQT7

(Anderson’s disease)(Anderson’s disease)

Priori et al. Priori et al. Circ. Res. Circ. Res. 2005; 96 2005; 96

Ion Channel MutationsIon Channel Mutations

Loss of FunctionLoss of Function– SCN5A SCN5A

BrugadaBrugada– IKs IKs LQT1 LQT1– IKr IKr LQT2 LQT2

Gain of FunctionGain of Function– SCN5A SCN5A LQT3 LQT3 – IKs IKs Fam. A. Fam. A.

Fib., Fib., Short Short QTQT

– IKr IKr Short QT Short QT

44

00

11 22

33NN

aa

Ca > NaCa > Na

IKr & IKsIKr & IKs

Short QT Syndrome RxShort QT Syndrome Rx

Gaita et al. JACC. 2004;43:1494-9.Gaita et al. JACC. 2004;43:1494-9.– 6 pts. from 2 different families.6 pts. from 2 different families.– Drugs: Flecainide (IV or oral), Drugs: Flecainide (IV or oral),

Sotalol, Ibutilide, and Sotalol, Ibutilide, and Hydroquinidine.Hydroquinidine.

Short QT Rx ResultsShort QT Rx Results

FlecainideFlecainide: slight inc. QT due to QRS : slight inc. QT due to QRS prolongation.prolongation.

Ibutilide & SotalolIbutilide & Sotalol: no change in QT: no change in QT HydroquinidineHydroquinidine::

– 5/6 pts- QTc normalized (2905/6 pts- QTc normalized (290405ms)405ms)– EPS 5/5 pts- inc. VERP, no VF/VTEPS 5/5 pts- inc. VERP, no VF/VT– F/U 11 mos- 4/6 on hydroquinidine w/o F/U 11 mos- 4/6 on hydroquinidine w/o

sx or arrhythmias detected by ICD.sx or arrhythmias detected by ICD.

Ventricular ERPVentricular ERP

QuinidineQuinidine

VW ClassVW Class: Ia (sodium channel blocker): Ia (sodium channel blocker) BlocksBlocks: INa, IKr, IKs, Ito, L-type Ca2+, : INa, IKr, IKs, Ito, L-type Ca2+,

IK1(in.rect.), & IKATP IK1(in.rect.), & IKATP QT increase. QT increase. Adverse effectsAdverse effects: diarrhea, SLE, : diarrhea, SLE,

thrombocytopenia, hepatitis, thrombocytopenia, hepatitis, cinchonism (tinnitus/HA), TdP, many cinchonism (tinnitus/HA), TdP, many drug interactions 2/2 block of CYP2D6.drug interactions 2/2 block of CYP2D6.

ICDICD

First line therapyFirst line therapy Risk of inappropriate shock Risk of inappropriate shock

delivery- Tw oversensing (delivery- Tw oversensing (Schimpf et Schimpf et

al. al. JCEJCE. 14: Dec 2003. 14: Dec 2003))

- Ventricular ERP- <150ms- Ventricular ERP- <150ms - induction of VF- induction of VF

- Atrial ERP- 120ms- Atrial ERP- 120ms

CirculationCirculation. 2003; 108. 2003; 108

Family TreeFamily Tree

39 yo39 yo

CirculationCirculation. 2003; 108. 2003; 108

8 mo8 mo

49 49 yyoo

39 yo39 yo

Schimpf, et al. Schimpf, et al. Heart Rhythm.Heart Rhythm. 2004;22004;2

SummarySummaryShort QT SyndromeShort QT Syndrome

Significantly short QTc <= 300ms.Significantly short QTc <= 300ms. Tall & peaked T-waves.Tall & peaked T-waves. Clinical: palpitations, syncope, SCD.Clinical: palpitations, syncope, SCD. Significant FHX of SCD.Significant FHX of SCD. Atrial and ventricular arrhythmias.Atrial and ventricular arrhythmias. Structurally normal hearts.Structurally normal hearts. Treatment: ICD and/or Quinidine.Treatment: ICD and/or Quinidine.