1. SUDDEN DEATH IN VARIOUS POPULATIONS: IS GENDER A RISK FACTOR? 11 th International Symposium Heart Failure & Co Reggia di Caserta; April 29, 2011; 12:35 P.M. Maria Rosa Costanzo, M.D., F.A.C.C, F.A.H.A Medical Director, Midwest Heart Specialists Heart Failure and Pulmonary Arterial Hypertension Programs Pulmonary Arterial Hypertension Programs Medical Director, Edward Hospital Center for Advanced Heart Failure Naperville, Illinois, U.S.A.

2. Incidence of SCD by Age and Gender Kannel WB et al. Am Heart J 1998; 136:205

3. Prospective Study of SCD in Women in the U.S. Albert CM et al. Circulation 2003;107; 2096-101 Relative Risk of SCD by Age % of Cardiac Deaths Deemed SCD by Age

4. Structural Heart Disease in Cardiac Arrest Survivors Albert CM et al. Circulation 1998; 93: 1170-6

5. Factors Associated with PEA vs. VT/VF The Oregon Sudden Unexpected Death Study OR (95% CI)* Age (per y ↑) 1.02 (1.01-1.04) White 1.0 (reference) Black 2.64 (1.29-5.38) Hispanic 0.32 (0.05-2.13) Asian 0.88 (0.20-3.98) Other Race 1.03 (0.23-4.59) CAD 0.35 (0.23-0.53) Hyperlipidemia 0.59 (0.38-0.90) Hx. Syncope 2.64 (1.31-5.32) Male, No Pulm. Dis 1.0 (reference) Female, No Pulm. Dis 1.68 (1.01-2.82) Male, Pulm. Dis. 3.17 (1.86-5.42) Female, Pulm. Dis 2.11 (1.10-4.04) Multivariable Odds Estimates of Factors Associated with PEA vs. VF/VT Teodorescu C. et al. Circulation 2010; 122: 2116-22 % of Patients

6. Basic Electrophysiological Variables Affected by Gender Differences Cardiac Cycle QT IntervalHeart Rate T Wave Morphology QT-RR Relationship QT Dispersion Higher Prevalence in Females Higher Prevalence in Males Congenital Long QT Syndrome AF Acquired Long QT Syndrome WPW AV Nodal Re-Entrant Tachycardia SCD

7. Sex-Related Differences in Repolarization Action Potentials from Isolated Guinea Pig Ventricular Myocytes Baseline and Ibutilide-Induced QTc Change in Normal Volunteers Rodriguez I et al. JAMA 285: 1322-6James MJ et al. Basic Res Cardiol 2004;99: 183-92

8. Relationship between Baseline QT Interval and Cycle Length Orchiectomy (Placebo) Orchiectomy + Dihydrotestosterone Liu XK et al. Cardiovasc Res 2003; 57:28-36

9. Effects of Dofetilide on APD and Incidence of EADs at a Cycle Length of 1000 ms in Rabbit RV Endocardial Papillary Muscles Female Male Ovariectomized Females Orchiectomized Males Pham TV et al. Circulation 2001; 103:2207-12

10. Effects of Dihydrotestosterone on Dofelitide-Induced Repolarization Changes in Rabbit RV Endocardial Papillary Muscles Males Orchiectomized Males DHT-Orchiectomized Males Females DHT Females APDEAD Pham TV et al. Circulation 2002; 106:2132-6

11. % Patients Age, Y James AF et al. Prog Biophysics Molecular Biol 2007; 94: 265-319

12. High Risk Subsets for ACA or ACA by Age Groups Goldenberg I et al. Curr Prob Cardiol 2008; 33: 629-94 Age Group (Years) High Risk Subsets BB Effect in High Risk Patients: % Reduction (p value) % Reduction (p value) Childhood (1-12) (1-12) Males with prior syncope and/or QTc >500 ms Females with prior syncope 73 (0.002) Adolescence (13-20) (13-20) Males and Females with either one or two or more of the following: QTc ≥ 530 ms ≥ episode of syncope in the past year ≥ 2 episodes of syncope in the past 2-10 y 64 (0.01) Adulthood (20-40) (20-40) Either one or more of the following: Female Gender Interim Syncope after age 18 QTc ≥ 500 ms 60 (< 0.01) (41-60) (41-60) Female gender Syncope in the past 10 y QTc ≥ 500 ms LQT3 genotype 42 (0.40) (61-75) (61-75) Syncope in the past 10 y 86 (0.05)

13. Probability of ACA or SCD in 3,774 LQTS Patients from the International LQTS Registry

14. Rashba EJ et al. Circulation 1998; 97: 451-6 % of Patients

15. Lehman MH et al. Am J Cardiol 1999;83: 354-9 JTc (msec)

16. Lethal Arrhythmias Susceptibility and Myocardial Connexin-43 Expression Knezl V. et al. Neuroendocrinology Letters 2008; 29: 798-601

17. Gender Differences in the Clinical Manifestations of the Brugada Syndrome No Events Events P value No Events Events P value Sx. At Dx. 46 (19) 20 (64) < 0.001 15 (15) 1 (33) NS Previous AF n (%) 18 (7%) 8 (26) 0.005 12 (11) 2 (67) 0.04 Spont. Type -1 ECG 105 (43) 21 (67) 0.01 23 (21) 2 (67) 0.04 PR (ms) 175 ± 30 178 ± 40 NS 173 ± 32 240 ± 62 0.001 QRS (ms) 107 ± 17 110 ± 18 NS 97 ± 16 130 ± 62 NS QTc (ns) 421 ± 48 432 ± 42 NS 420 ± 49 486 ± 47 0.006 ST elev. 3.6 ± 2 3 ± 1 NS 2.4 ± 1 3.2 ±1 NS VF Inducibility (%) 2874 < 0.001 1150NS HV Interval 48 ± 10 46 ± 7 NS 46 ± 8 60 ± 11 0.002 Benito, B. et al. J Am Coll Cardiol 2008;52:1567-1573 MalesFemales

18. Benito, B. et al. J Am Coll Cardiol 2008;52:1567-1573 Kaplan-Meier Estimate of Cardiac Event-Free Survival According to Gender The Brugada Syndrome and GenderHR 95% CI P Value Gender2.820.64-12.41NS Previous AF 2.160.93-5.030.007 Syncope at Dx. 1.860.7-4.97NS Aborted SCD 8.453.17-22.55<0.001 Spont. Type 1 ECG 1.40.59-3.33NS VF Inducibility 2.931.14-7.550.02

19. ICD Trials

20. Multivariable Predictors of ICD Use Variable HR-Primary Prevention Cohort HR-Primary Prevention Cohort HR-Secondary Prevention Cohort Age, per y 0.930.95 Male sex 3.152.44 Black race 0.850.71 Comorbidities CBV0.910.97 Chronic Pulm. 0.890.98 CAD3.115.33 Dementia0.290.32 DM1.021.10 HTN0.851.04 Cancer0.590.36 Renal0.980.90 Midwest Region 1.171.22 Northeast1.191.10 Year of Implant 20001.191.15 20011.571.38 20022.24 1.81 1.81 20032.921.94 20043.592.04 20054.882.05 Adapted from Curtis LH et al. JAMA 2007; 298: 1517-24

21. 1 Year Mortality by ICD Use and Gender in a Large Medicare Population No. of Pts. At Risk % Mortality with ICD % Mortality without ICD HR (p value) (p value) Overall9699010.413.41.01 Men4772911.213.11.05 Women492617.813.70.93 No. of Pts. At Risk % Mortality with ICD % Mortality without ICD HR (p value) (p value)Overall5434210.916.8 0.65 (0.001) Men2933311.016.8 0.62 (0.001) Women2500910.816.00.71(0.001) Primary Prevention CohortSecondary Prevention Cohort Adapted from Curtis LH et al. JAMA 2007; 298: 1517-24

22. Effectiveness of ICD for the Primary Prevention of SCD in Women with Advanced HF Baseline Characteristics of Patients in Trials Included in the Meta-Analysis Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6

23. Effectiveness of ICD for the Primary Prevention of SCD in Women with Advanced HF Sex Differences in Mortality Rates Between ICD and Medical Therapy Groups Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6

24. Effectiveness of ICD for the Primary Prevention of SCD in Women with Advanced HF MEN WOMEN Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6

25. 161.470 pts, 27% women Gender Differences in Procedure-Related Adverse Events in Patients Receiving ICD Therapy Peterson PN et al. Circulation 2009; 119: 1078 - 84

26. Benefits of ICD in Women No trial powered to separately examine outcomes in men and women or test for difference in ICD effectiveness Small numbers of women enrolled Limited post-hoc analyses for females do not clearly demonstrate a mortality benefit: – SCD-HeFT: benefit not clear (not powered for gender) – MADIT II: nonsignificant trend toward lower mortality in females but analysis limited by too few female subjects Meta-analysis: 934 females in 5 trials; no difference in all-cause mortality for women with ICD vs medical Rx

27. ■ Females with lower rates of SCD than males ■ Differences in arrhythmia susceptibility ■ 30% of ICDs are implanted in females ■ Even though the benefit is less, it may represent a clinically significant reduction in deaths Conclusions

28. Conclusions A trial targeting women is needed To detect the same ICD benefit in women as was observed in men with 90% power and α=0.05, a study larger than SCDHeFT would be required (1.585 women in each treatment arm, 3.170 total) It may now even be considered “unethical” to withhold ICD therapy in women meeting the SCD-HeFT enrollment criteria.