1. Sudden Death in Coronary Disease: Who is Most Susceptible
Sudden Death in Coronary Disease: Who is Most Susceptible? Oklahoma City, April 3, Sumeet S. Chugh MD Associate Director, Heart Institute Section Chief, Clinical Electrophysiology Price Chair in Cardiac Electrophysiology Research Cedars-Sinai Medical Center Professor of Medicine, UCLA

2. Etiologies of Sudden Cardiac Death
10-15
5-10 80
Coronary Disease
Other: LQTS, Brugada , IVF, Congenital...
Cardiomyopathies

3. Mechanisms of Sudden Coronary Death
Acute: Thrombosis
Chronic: Scar-related arrhythmia
Postulated: Ischemia is the trigger in a patient who is susceptible due to genetic/other factors

4. Acute Coronary Thrombosis
Davidson.

5. Virmani et al. Arterosclerosis Thromb Vasc Biol 2000;1262; American J Med 2009:122:S10.

7. Prognosis After Myocardial Infarction LVEF: Determinant of Overall Mortality
1-year
cardiac
mortality
(%)
Radionuclide EF (%)
<20%
20-39%
40-59%
60%
n=799
Mean EF = 46%
No. 21
244
382
152
NEJM 1983;309(6):331-6 7

8. SCA  Potential for Prevention Significant Magnitude, Insignificant Survival
USA – ,000/yr
10-15% of all deaths
Survival  5%
AEDs  10%
Zheng ZJ, Croft JB, Giles WH, Mensah GA. Circulation 2001;104(18):
Chugh SS, et al. J Am Coll Cardiol 2004; 44 (6):

9. Moss A, et al. Circulation 2004;110:3760-3765
ICD is Best Available Prevention Modality But Minority of Patients Actually Use It DC
SCD-HEFT: Appropriate shocks in 20%
MADIT II- Similar rate
Moss A, et al. Circulation 2004;110:
Bardy GH, et al. NEJM Jan 2005; 352: 9

10. Rapid Increase of ICD Implants Life-saving, but Expensive
US Data
Treat 15  save 1
US 65y+  K patients/yr
Cost $ 3-6 billion/yr
Jauhar & Slotweiner. NEJM 2004;351: 10

11. Need for Improved Assessment of Risk Find the Patient that will Benefit the Most
In the general population, some presently asymptomatic individuals will have future SCA. Can we screen to identify those at risk? 11

12. Other Predictors of SCA (Cohort Studies)
Diabetes Mellitus  2.3-fold  risk
Obesity  1.6-fold  risk
Long QT interval  2-fold  risk
No studies in general population
Algra A, et al. Circ 1991;83(6):
Albert CM, et al. Circ 2003;107(16):
Jouven X, et al. Circulation 1999;99(15):

13. Family History  Predictor of SCA
Seattle study 1.57-fold  SCA risk
Paris Prospective study 1.8-fold  risk; 9-fold if both parents had SCA
Friedlander Y, et al. Circulation 1998; 97:155-60
Jouven X, et al. Circulation 1999;99(15):

14. SCD Occurrence in Surviving Twins Monozygotic Vs. Dizygotic
Chugh SS et al. Heart Rhythm 2004;1(1) Suppl:S86
Log-rank test P=0.0019 14

15. SCA  Significant Genetic Component
2-fold higher risk of SCA in MZ twins
All age- groups; male predominance
Male MZ co-twins fold  risk
Chugh et al. Heart Rhythm 2004;1(1) Suppl:S86 15

16. Most SCAs Occur in the Field Not the Clinic, Ward or Hospital
100
200
300
x1,000
Incidence (%/Year)
Total SCDs (No./Year)
General
population
Multirisk subgroup
Previous
Cor. event
EF <35% or heart failure
VF/VT
survivors
Post-MI
subgroups 1 2 5 10 20
SCD-HeFT
AVID
CIDS
MADIT I 40 30
MUSTT
DEFINITE
Ore-SUDS
Myerburg RJ, et al: Circulation 1998;97: 16

17. Hypothesis Ischemia is the trigger for SCD in a patient
who is susceptible due to genetic or
other factors

18. * The Oregon Sudden Unexpected Death Study
Portland, Oregon USA, (Pop. 1 million)
Feb 1, 2002 6th Year *
Chugh SS, et al. J Am Coll Cardiol 2004; 44 (6): 18

19. 19

20. Community-Based Prospective Approach to SCD
Genome/Proteome/Tissue Bank
Epidemiology Family History
Detailed Phenotyping
First Responders
Hospitals
Med. Examiner
Retrieval of clinical records
Review of autopsies
In-house adjudication for SCD
Presumed SCDs (n>2500)
SCDs (n>2000)
Chugh SS, et al. J Am Coll Cardiol 2004; 44 (6): 20

21. Geographically Matched Control Populations
Alive
No History of Cardiac Arrest
Source: First Responders,
Clinic, Hospital, M. Examiner
Blood samples
DNA archive (n>750)
Phenotyping
Detailed cardiac structure
(echo, angiogram etc), Clinical History, EKG + 21

22. US and Global Incidence of SCD51 60 56
USA: ,000 cases/yr
World : 4-5 million cases/yr
Chugh SS, et al. J Am Coll Cardiol 2004; 44 (6):
Byrne R, et al. Eur Heart J 2008.
Vaillancourt C, Stiell IG. Can J Cardiol 2004;20(11): 22

23. SCD More Common with Advancing Age 41% age <65 years; 40% female23

24. LV Dysfunction: Best Available Predictor How Much Does it Contribute to SCD?
Normal
(EF ≥ 0.55)
48%
Severely reduced
(EF ≤ 0.35)
32%
Mild-moderately reduced
(EF )
20%
Stecker EC……Chugh SS. J Am Coll Cardiol 2006; 47 (6):
Retrospective, n=121 (17%)

25. Poor Effectiveness of Current Guidelines for Prevention of SCA
100
200
300
x1,000
Total SCDs (No./Year)
SCD-HeFT
AVID
CIDS
MADIT I
MUSTT
Ore-SUDS
DEFINITE
None had ICD
Ideal scenario, current indications- 35% would meet criteria for ICD
65% - missed by current guidelines
Stecker EC……Chugh SS. J Am Coll Cardiol 2006; 47 (6): 25

26. Clegg S……Chugh SS. Heart Rhythm May 2008
Equal Opportunity for SCD Prevention? Prevalence of Severe LVD  in Women
Oregon SUDS
Men
64%
Women
36%
LV Ejection Fraction
Males vs. Females
37%
50%
27%
31%
19%
Normal
(EF>=55%)
Moderately
Reduced
(EF 36 -
54%)
Severely
(EF <=35%) 50 40 30 20 10
Men
Women
Clegg S……Chugh SS. Heart Rhythm May 2008 26

27. Look Beyond the Ejection Fraction

28. Straus SMJM, et al. J Am Coll Cardiol 2006;47:362–7
Prolonged QTc: Independent Risk Factor Rotterdam Cohort Study 3-fold  risk, 8-fold if age<68 y
Straus SMJM, et al. J Am Coll Cardiol 2006;47:362–7 28

29. Ore-SUDS: QTc in SCD vs. CAD n=682 (373 cases, 309 controls)
450
433
Abnormal QTc (p<0.0001)
Chugh SS, et al. Circulation 2009 (In Press) 29

30. Determinants of QTc in CAD
QTc Predictors
Adjusted mean
p-value
Gender
0.01
Male
435
Female
446
Diabetes
Yes
437 No
428
QT  Drugs
0.08 (Interaction)
436
Chugh SS, et al. Circulation 2009 (In Press)

31. Idiopathic  QTc Powerful Predictor 6-Fold  Risk of SCD in CAD
Chugh SS, et al. Circulation 2009 (In Press) 31

33. Chugh SS, et al. Circulation Nov 2007
Echocardiographic LV Mass Higher in Cases vs. Controls (n=460 patients)
125
245
p=0.02
p=0.007
214
107
Gms
Gms/m2
Chugh SS, et al. Circulation Nov 2007

34. Kennedy GC, et al. Nature Biotechnology 2003;10(21):1233-37
Common Disease, Common Variant Approach Microarrays for SNP sets & GWAS Discovery & Validation of Novel SCN5A Modifier
Kennedy GC, et al. Nature Biotechnology 2003;10(21): 34 34

35. Case Control 2 Compare marker allele frequency
Identify disease associated regions
ACGGGAGATGATG T
ACGTCC
Regulatory elements:
3% of the genome
Coding elements:
1.5% of genome
Identify gene functional elements in associated regions
(Cross-species comparisons)
Identify causal variant(s)
Genome-wide
genotyping 1 2 3 4
Arking, Chugh, Chakravarti & Spooner.
Circ Res 2004;94(6):712-23 35 35

36. Susceptibility to SCD LV dysfunction in Minority, Predictors Diverse
Genome
Environment
Psych. Stress
Smoking
Particulate
Matter
Diet
CHF
QTc
Vulnerable Plaque
LVH
Other Factors
Socioeconomic
status DM 36 36

37. Current and Future Trends for Mortality Due to SCD
ASA, Lipids, PTCA, Prevention
DM, Obesity 
 CAD,  CHF,  SCD
Rate/100,000 Pt/yrs
Fox CS et al. Circ 2004;110: 37

38. Identifying Susceptibility to SCD Toward Prediction of Individual Risk
Present
Future
LV EF <35%, ischemic & non-ischemic
Survived SCA or sustained VT, no obvious reversible conditions
All ranges of LVEF
Vulnerable plaque
Genetic risk
LVH
 QTc interval
Diabetes
Obesity 38