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VULNERABLE
PATIENT
SYMPOSIUM
SCA Risk Factors:
What are the triggers?
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;
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;
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
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
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.
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
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
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
Atrial pre-excitation when His is refractory established
presence of a concealed accessory pathway
Early A
AHJ 103:426-30, 1982
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
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
OPTICAL MAPPING
Di-4-Anepps and cytochalasin D
Asymmetrical conduction initiated by epi- & endocardial
stimulation during acute ischemia
“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
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
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?
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
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?
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

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Vulnerable patient mar 04

  • 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
  • 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

Notes de l'éditeur

  1. Studies have identified several factors that increase a patient’s risk for SCA. Individual risk factors are more predictive of SCA if they are combined with other risk factors. NOTE: Slides are provided on each risk factor if additional information is desired.
  2. These results come from the MADIT-II study. Mortality risk in contemporary post- MI pts with EF &amp;lt; 30% tends to increase as a function of time from last MI. Correspondingly, survival benefit from the ICD increases significantly with time, up to 15 years following MI. Mortality risk in contemporary post- MI pts with EF &amp;lt;30% tends to increase as a function of time from last MI.
  3. Very few of the SCA victims in this recently published study were found to have an acute MI cause. The study also identified that the median time to a sudden cardiac arrest event was many years (9 years) after a MI event.