VULNERABLE PATIENT

SYMPOSIUMSCA 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 failure3. 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 fibrillation7. Smoking8. Obesity, DM9. 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 Temperature17 Perfusion patterns: MRI18 Heart rate turbulence

STANDARD NEW

26.7

22.1

15.815.6 16.915.3

9.8

13.8

0

5

10

15

20

25

30

1-17 mo 18-50 mo 51-121 mo > 121 mo

ConvICD

(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

% M

ort

alit

y

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/FUNCTIONALSUBSTRATESUBSTRATE

TRANSIENT INITIATINGTRANSIENT INITIATINGEVENTSEVENTS

ARRHYTHMIA MECHANISMSARRHYTHMIA MECHANISMS

Coronary artery diseaseCoronary artery diseaseCardiomyopathyCardiomyopathy

DilatedDilatedHypertrophicHypertrophic

Right ventricular dysplasiaRight ventricular dysplasiaValvularValvularCongenitalCongenitalPrimary electrophysiologicalPrimary electrophysiologicalNeurohumeralNeurohumeralDevelopmentalDevelopmentalInflammatory, infiltrative, Inflammatory, infiltrative,

neoplastic, degenerative, toxicneoplastic, degenerative, toxic

Neuro/endocrineNeuro/endocrineDrugsDrugsElectrolytes, pH, pO2Electrolytes, pH, pO2Ischemia/reperfusionIschemia/reperfusionHemodynamicHemodynamicStretchStretchArising/Stress/SleepArising/Stress/SleepALCOHOLALCOHOLEMDEMD

AsystoleAsystoleVTVTVFVF

ReentryReentryAutomaticityAutomaticityTriggered activityTriggered activityBlock/cell-to-cell uncouplingBlock/cell-to-cell uncoupling

Zipes and Wellens Circ 1998; 98:2334

Zipes, WellensSudden Cardiac DeathCirculation 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 ALTERSCONDUCTIONBY A FEW MSECCAN PRECIPITATETACHYCARDIAIN 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 WuKrannert Institute of Cardiology, Indiana Univ. Sch. of

Medicine

IN PRESSCARDIOVASCULAR 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