Sudden Death in Coronary Disease: Who is Most Susceptible Sudden Death in Coronary Disease: Who is Most Susceptible? Oklahoma City, April 3, 2009 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

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

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

Acute Coronary Thrombosis Davidson. http://www.ajmc.com/supplement/managed-care/

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

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

SCA  Potential for Prevention Significant Magnitude, Insignificant Survival USA – 250- 300,000/yr 10-15% of all deaths Survival  5% AEDs  10% Zheng ZJ, Croft JB, Giles WH, Mensah GA. Circulation 2001;104(18):2158-63 Chugh SS, et al. J Am Coll Cardiol 2004; 44 (6): 1268-75

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;110:3760-3765 Bardy GH, et al. NEJM Jan 2005; 352:225-237 9

Rapid Increase of ICD Implants Life-saving, but Expensive US Data Treat 15  save 1 US 65y+  50-100K patients/yr Cost $ 3-6 billion/yr Jauhar & Slotweiner. NEJM 2004;351:2542-44 10

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

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):1888-94. Albert CM, et al. Circ 2003;107(16):2096-101. Jouven X, et al. Circulation 1999;99(15):1978-83.

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):1978-83

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

SCA  Significant Genetic Component 2-fold higher risk of SCA in MZ twins All age- groups; male predominance Male MZ co-twins 12-32 fold  risk Chugh et al. Heart Rhythm 2004;1(1) Suppl:S86 15

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;97:1514-21 16

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

* 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): 1268-75 18

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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): 1268-75 20

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

US and Global Incidence of SCD 51 60 56 USA: 180-250,000 cases/yr World : 4-5 million cases/yr Chugh SS, et al. J Am Coll Cardiol 2004; 44 (6): 1268-75 Byrne R, et al. Eur Heart J 2008. Vaillancourt C, Stiell IG. Can J Cardiol 2004;20(11):1081-90. 22

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

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 0.36-0.54) 20% Stecker EC……Chugh SS. J Am Coll Cardiol 2006; 47 (6): 1161-6 Retrospective, n=121 (17%)

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): 1161-6 25

Clegg S……Chugh SS. Heart Rhythm May 2008 Equal Opportunity for SCD Prevention? Prevalence of Severe LVD  in Women Oregon SUDS 2002-2006 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

Look Beyond the Ejection Fraction

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

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

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)

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

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

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):1233-37 34 34

Case Control 2 Compare marker allele frequency Identify disease associated regions .3 .3 .4 .4 .8 .3 .4 .2 .6 .6 .3 .7 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

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

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;110:522-527 37

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