This document discusses triggers for sudden cardiac arrest (SCA) and death (SCD). It notes that over 2/3 of SCD cases are unable to be predicted due to a lack of well-established risk factors. While population risk factors can identify at-risk groups, they cannot predict risk for individuals. The document explores various biological, anatomical, and environmental factors that can precipitate fatal arrhythmias and discusses how the timing of transient initiating events is critical for the development of ventricular tachyarrhythmias. It emphasizes that myocardial electrophysiological processes likely determine the onset or lack of VT/VF/SCD and that immediate access to automated external defibrillators is needed to save lives.

1. VULNERABLE
PATIENT
SYMPOSIUM
SCA Risk Factors:
What are the triggers?

2. SOBERING STATS
• 30-50% SCD that are due to CAD occur as first
cardiac event
• 1/3 SCD occur in pts with known CAD or risk
markers but power insufficient to be useful marker
• Only a small % have well established risk markers
(ICD trials)
• Therefore, >2/3 unable to predict
Zipes and Wellens Circ 1998; 98:2334; Myerburg JCE 2002; 13:709;

3. PROBLEMS WITH RISK
FACTORS
• LACK OF SPECIFICITY, SENSITIVITY,
PREDICTIVE ACCURACY
• ABLE TO IDENTIFY POPULATIONS AT RISK
BUT NOT INDIVIDUAL
• Present risk factors identify risk of developing SHD
rather than proximate precipitator
• Need individual-specific predisposition: single
patient probabilities, not population predictions
• Lack insight into mechanisms of SCD
Zipes and Wellens Circ 1998; 98:2334; Myerburg JCE 2002; 13:709;

4. Risk Factors for SCA
1. Previous Sudden Cardiac Arrest Event
or Prior Episode of Ventricular
Tachyarrhythmia (VT)
2. Decreased LVEF and heart failure
3. Previous Myocardial Infarction
(MI)/Coronary Artery Disease (CAD)
4. Ventricular Ectopy in Chronic
Ischemic Heart Disease; PVCs during
recovery from TME
5. EP/ECG parameters: QTc. QRSd,
HRV, BRS, EPS, TWA, SAECG, QT
dispersion
6. Atrial fibrillation
7. Smoking
8. Obesity, DM
9. Inactivity
10 Fatty acid metabolism:
mitochondrial defects
11 Serum biomarkers:
cytokines, other proteins
12 Inflammation: (CRP),
troponin
13 Molecular markers: beta
receptor subtypes
14 Genetics: control of
substrate, thrombosis
precipitators, inherited
arrhythmias
15 Single nucleotide
polymorphisms (SNPs): ion
channels, other
16 Temperature
17 Perfusion patterns: MRI
18 Heart rate turbulence
STANDARD NEW

5. 26.7
22.1
15.815.6 16.9
15.3
9.8
13.8
0
5
10
15
20
25
30
1-17 mo 18-50 mo 51-121 mo > 121 mo
Conv
ICD
(n = 296) (n = 284) (n = 290) (n = 289)
Hazard Ratio 1.08
(p = 0.81)
0.56
(p < 0.001)
0.56
(p< 0.001)
0.56
(p < 0.001)
David J. Wilber MD, NASPE 2003. Abstract ID. 100865
Time Dependence of Mortality Risk
Post-MI: MADIT-II
Time from MI
%Mortality

6. Time Dependence of Mortality
Risk Post-MI
Maastricht Circulatory Arrest Registry:
– In 224 SCA victims, only 4% were
due to an acute MI.
– The median time from MI to SCA
was 9 years in 92 patients
(41% of total).
Gorgels PMA. European Heart Journal. 2003;24:1204-1209.

7. WHAT TRIGGERS SUDDEN
CARDIAC DEATH?
“Why Did He Die On Tuesday
and Not On Monday? Or On
Wednesday?”
Adapted from an editorial (Zipes
DP Less heart is more. Circulation
107:2531, 2003) for a paper on
ventricular remodeling by Pfeffer
and Braunwald

8. ANATOMIC/FUNCTIONALANATOMIC/FUNCTIONAL
SUBSTRATESUBSTRATE
TRANSIENT INITIATINGTRANSIENT INITIATING
EVENTSEVENTS
ARRHYTHMIA MECHANISMSARRHYTHMIA MECHANISMS
Coronary artery diseaseCoronary artery disease
CardiomyopathyCardiomyopathy
DilatedDilated
HypertrophicHypertrophic
Right ventricular dysplasiaRight ventricular dysplasia
ValvularValvular
CongenitalCongenital
Primary electrophysiologicalPrimary electrophysiological
NeurohumeralNeurohumeral
DevelopmentalDevelopmental
Inflammatory, infiltrative,Inflammatory, infiltrative,
neoplastic, degenerative, toxicneoplastic, degenerative, toxic
Neuro/endocrineNeuro/endocrine
DrugsDrugs
Electrolytes, pH, pO2Electrolytes, pH, pO2
Ischemia/reperfusionIschemia/reperfusion
HemodynamicHemodynamic
StretchStretch
Arising/Stress/SleepArising/Stress/Sleep
ALCOHOLALCOHOL
EMDEMD
AsystoleAsystole
VTVT
VFVF
ReentryReentry
AutomaticityAutomaticity
Triggered activityTriggered activity
Block/cell-to-cell uncouplingBlock/cell-to-cell uncoupling
Zipes and Wellens Circ 1998; 98:2334
Zipes, Wellens
Sudden Cardiac Death
Circulation 1998

9. 40 yo man developed incessant SVT after
second MI and development of RBBB
Prystowsky, Heger, Jackman, Naccarelli and Zipes AHJ 103:426-30, 1982
Spontaneous onset SVT
Rate 74 bpm Rate 81 bpm

10. Atrial pre-excitation when His is refractory established
presence of a concealed accessory pathway
Early A
AHJ 103:426-30, 1982

11. HV interval 50 ms: AP refractory
HV interval 90 ms post RBBB:
AP conducts and SVT is initiated.
AHJ 103:426-30, 1982
81 bpm74 bpm
REMODELING REMODELING
THAT ALTERS
CONDUCTION
BY A FEW MSEC
CAN PRECIPITATE
TACHYCARDIA
IN A SUBSTRATE
PRESENT BUT
DORMANT FOR
YEARS

12. WHY DO SOME PVCs INDUCE VT
BUT OTHERS DO NOT?
EPICARDIUM IS MORE SENSITIVE
TO THE EFFECTS OF ISCHEMIA
THAN IS THE ENDOCARDIUM.
Transmural Reentry Triggered by Epicardial
Stimulation during Acute Ischemia in Canine
Ventricular Muscle
Wu J, Zipes DP
American Journal of Physiology
283: H2004-11, 2002

13. OPTICAL MAPPING
Di-4-Anepps and cytochalasin D

14. Asymmetrical conduction initiated by epi- & endocardial
stimulation during acute ischemia

15. “WINDOWS OF
OPPORTUNITY DURING
ISCHEMIA”
TIMING IS CRITICAL FOR DEVELOPMENT
OF REENTRANT VT v. NONE
EPICARDIAL v. ENDOCARDIAL PVCS
Heterogeneity precludes safe and
effective pharmacotherapy but
supports benefits of ICDs

16. Optical Mapping of the
Functional Reentrant Circuit of
Ventricular Tachycardia in Acute
Myocardial Infarction
Jianyi Wu, MD
Tamana Takahashi, MD
Pascal van Dessel, MD, PhD
William Groh, MD
John Miller, MD
Douglas P. Zipes, MD
SUBMITTED FOR PUBLICATION

17. Therefore, timing and activation
sequence determine whether or
not VT/VF will occur after MI.
But, can ischemia predispose to
VT/VF via other mechanisms?

18. Prior ischemia enhances
arrhythmogenicity in isolated
canine ventricular wedge model of
Long QT 3
Norihiro Ueda, Douglas P. Zipes, Jiashin Wu
Krannert Institute of Cardiology, Indiana Univ. Sch. of
Medicine
IN PRESS
CARDIOVASCULAR RESEARCH

19. Conclusions
A prior episode of acute ischemia, even
after apparent electrophysiologic
recovery, enhances the arrhythmogenicity of
ATX II (LQT3 model) through the
development of EADs and reentry.
CAN ISCHEMA “SENSITIZE” PATIENTS
WITH LQTS, OR OTHER DISEASE
STATES, TO DEVELOPING SCD?

20. TRIGGERS
• MYOCARDIAL EP PROCESSES
PROBABLY DETERMINE ONSET/LACK
OF VT/VF/SCD
• DIFFICULT TO MEASURE CLINICALLY;
INDIRECT EP SURROGATES
• MUST CONTINUE TO RELY ON OTHER
INDIRECT RISK FACTORS FOR NOW
• BUT MUST HAVE AED DEPLOYMENT
FOR IMMEDIATE RESPONSE TO SAVE
LIVES IN THE FORSEEABLE FUTURE