Profiles in Prognosis for HCM

Japan N=3,354;20-77 y 0.17% CARDIA N=4,111; 23-35 y 0.17% Rural Minnesota N=15,137; 16-87 y 0.19% Amer Indians N=3,501;51-77 y 0.2% General Population 1:500 China N=8,080; 18-74 y 0.16% 600,000 people in U.S. AT RISK: 50,000 100,000? Profiles in Prognosis for HCM Sudden Death Risk Symptom Progression End- Stage AF

Arrhythmogenic Myocardial Substrate in HCM Maron BJ et. al. Circulation 2000; 102:858 % HCM Mortality Per Age Group 16 14 12 10 8 6 4 2 0 Sudden Stroke Heart Failure 5-15 16-25 26-35 36-45 46-55 56-65 66-75 >75 Age at Death or Most Recent Evaluation (years)

2 prevention Cardiac arrest/sustained VT 1 prevention Familial sudden death Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response Massive LVH Potential arbitrators End-stage phase LV apical aneurysm Marked LV outflow obstruction (rest) Extensive delayed enhancement Modifiable Intense competitive sports CAD Alcohol septal ablation (?) Mutations ± Highest Intermediate Lowest ICD

% Patients With SCD 16 14 12 10 8 6 4 2 0 Relation Between LV Thickness & SCD in 480 HCM Patients <15 16-19 20-24 25-29 30 Max. LV Wall Thickness (mm) Spirito et. al. NEJM 2000; 342:1778 2 prevention Cardiac arrest/sustained VT 1 prevention Familial sudden death Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response Massive LVH Potential arbitrators End-stage phase LV apical aneurysm Marked LV outflow obstruction (rest) Extensive delayed enhancement Modifiable Intense competitive sports CAD Alcohol septal ablation (?) Mutations ± Highest Intermediate Lowest ICD

A P VS D B P Maron MS et. al. Circulation 2008; Figure 118:1541 1. D C VS P D LA D E F * * * * * * Patients with LVAA (n=28) Maron MS et. al. Circulation 2008; 118:1541 Alive/ Clinically Stable (n = 16)* Adverse Events (n = 12) non-fatal embolic stroke (1) Sudden Death (2)* Aborted Cardiac Arrest (2) Progressive Heart Failure/ Death (5) Appropriate ICD Discharge (3)* non-fatal embolic stroke (1) Cardiovascular Event Rate = 11%/year

2 prevention Cardiac arrest/sustained VT 1 prevention Familial sudden death Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response Massive LVH Highest ICD Potential arbitrators End-stage phase LV apical aneurysm Marked LV outflow obstruction (rest) Extensive delayed enhancement Modifiable Intense competitive sports CAD Alcohol septal ablation (?) Mutations ± Intermediate Lowest Septal Scarring Post-ablation Post-myectomy Septal Scar VS=30% LV10% No Scar Valeti et. al. JACC 2007;49:350

% Patients With Sustained VT/VF/SD 30 25 20 15 10 5 0 Ventricular Tachyarrhythmias and Sudden Death Following Alcohol Septal Ablation 5% 37/386 = 10% 7% 10% 24% 25% Sorajja Cuoco Noseberry Maron van der Lee 2 prevention Cardiac arrest/sustained VT 1 prevention Familial sudden death Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response Massive LVH Highest ICD Potential arbitrators End-stage phase LV apical aneurysm Marked LV outflow obstruction (rest) Extensive delayed enhancement Modifiable Intense competitive sports CAD Alcohol septal ablation (?) Mutations ± Intermediate Lowest

Sudden Death in Young Athletes Other (5%) Possible HCM* ( 8%) HCM (36%) WPW (2%) Dilated CM (2%) AS (3%) Aortic Rupture (3%) CAD (3%) LAD Bridge (3%) MVP (4%) ARVC (4%) Ion Channel (4%) Myocarditis (6%) Coronary Anomalies (17%) Maron, BJ et. al. Circulation 2009; 119:1085-1092 Hypertrophic Cardiomyopathy Sarcomeric Protein Mutations Non-Sarcomeric Mutations ~ 11 Genes--- or more? > 1000 mutations AMP-Kinase (PRKAG2) Lamp2 (Danon) Storage Diseases Fabry Disease

Risk Stratification for Sudden Death in HCM Family history of sudden death Extreme LVH Nonsustained VT Unexplained syncope Abnormal BP response to Ex High Intermediate Moderate No risk factors Low Risk Multicenter Study on Sudden Death in Low Risk Patients with HCM Study population = 721 Low Risk patients Total number of sudden deaths = 22 Prevalence = 3% Incidence = 0.5%/yr

Foci For Ventricular Arrhythmias? VS LV RV 100 90 80 70 60 50 40 30 20 10 0 p<0.001 p=0.001 p=0.01 Any DE No DE p=0.06 % of HCM Patients with Arrhythmia 24-hour Holter Arrhythmia and Presence of DE NSVT Couplet PVC SVT Adabag et. al. JACC 2008; 51:1369

1.00 Presence of DE vs. Events Event-free rate 0.95 0.90 0.85 0.80 DE (+) DE (-) N=202 N = 202 Follow-up: avg 2 years p = 0.5 0 0.5 1 1.5 2 2.5 3 Follow-up Duration (years) Maron MS et. al. Circ HF 2008; 1:184 DE as the Only Risk Factor A B VS AML LV FW C Maron BJ et. al. AJC 2008; 101:544

Family T (as of 12-1-10) (40s) (85) (45) SCD (100) (73) (77) MyBPC + ctnl + No Risk Factors (39) MyBPC + ctnl + Survived CA 37 y (32) ctnl + (4) MyBPC + ctnl + ctnl MyBPC Arg145Trp Gln998Glu Prevention of Sudden Death In HCM

35 y Brother SD (age 39) 36 y ICD 5 y: 9 y: 40 y Generator replaced 41 y Appropriate shock #1 50 y Appropriate shock #2 53y Present HCM is Unpredictable

ICD in HCM: 2007 506 Follow-up = 3.7 ± 3 years 103 Appropriate Shocks VT/VF (20%) 5.5%/ yr ICD discharge rate 11% 4% 2º prevention 1º prevention Maron, BJ et. al. JAMA 2007;298:405 Rate of Appropriate Shocks (100 person-yr) 7 6 5 4 3 2 1 0 33% of appropriate shocks 3.7 3.0 Overall p=0.88 4.6 1 2 3 No. Risk Factors for Primary Prevention Maron, BJ et. al. JAMA 2007;298:405

One Risk Factor Patients With Primary Prevention Appropriate Shock Rates/Year 6 5 4 3 2 1 2.0 2.8 2.9 5.0 0 Massive LVH Family SD NSVT Syncope (Holter) Maron, BJ et. al. JAMA 2007;298:405 ICD in HCM : Time to First Shock 16 14 No. Patients 12 10 8 6 4 2 0 3 4-6 7-10 11-20 21-30 41-50 31-40 51-60 61-70 71-90 >90 Maron, BJ et. al. JAMA 2007;298:405 Duration (months)

Primary Prevention Decision Tree: ICD In HCM Risk Factors High-- risk? Some risk Cardiologist TRANSPARENCY / FULL DISCLOSURE / INFORMED CONSENT Patient Autonomy HCM ICD Registry 29 (6%) Deaths 14 No HCM HCM HCM- Arrhythmias (nl EF) 1 Cancer, sepsis, renal diseases, suicide, CAD, accidents 14 End-stage Embolic stroke ICD Malfunction Maron, BJ et. al. JAMA 2007;298:405

Risk Stratification and ICD Decision-Making in HCM Current risk factors are a useful guide 1 risk factor can be enough (but not obligatory) for ICD Risk factors cannot be summed numerically; all with low PPV Absence of risk factors does not confer immunity from SD ICD decisions may also be based on: individual physician judgment/patient autonomy Benign/Stable (normal longevity) Profiles in Prognosis for HCM Sudden Death Risk Symptom Progression End Stage AF ICD

High-Risk Children with HCM and ICDs Implanted < 20 years: Appropriate shocks: Age at intervention: Implanted < 15 years: Appropriate shocks: Age at intervention: 83 23 (28%;7%/y) 18 + 4 years 37 13 (35%;11%/y) 15 + 3.6 years

Bethesda Conference # 36 Recommendations Athletes with the unequivocal diagnosis of hypertrophic cardiomyopathy should not participate in most competitive sports, with the possible exception of those of low intensity. This recommendation includes those athletes with or without symptoms and with or without left ventricular outflow obstruction. A Echo B CMR RV VS * RV VS LV * * LV Maron MS et. al. in press

A 73y/F B 77y/M VS * * C 37y/M * * Family T After the Shock?

Trading SD for CHF Moss et. al. MADIT-II Circulation 2004; 110:3760-65 Clinical Status Post Appropriate ICD Shock I NYHA Class: Initial VT/VF 25 23 1 NYHA Class: At follow-up 25 1 90% II 5 4 4 2 III 2 1 3 Maron, BJ et. al. Heart Rhythm 2009; 6:993

A B VS Ao VS MAC C D A LV C VS * * RV VS D B E RV VS * * * * LV

Outcome of HCM Patients First Evaluated at 60 Years Old 70 65% 60 % of HCM Cohort 50 40 30 20 10 0 Alive 13% Non- Cardiac Death 12% Non-HCM Cardiac Death 2% 1% 1% Embolic Stroke Heart Failure HCM Death 0.2%/y SCD Management of HCM Key Elements Screening of relatives for HCM Risk assessment for prevention SCD Avoid competitive sports, volume depletion, isometric exercise Control exertional symptoms Older, asymptomatic patients Reassurance Surveillance Exclude HTN

Meta-Analysis of Presence DE and Adverse Cardiovascular Events Total Events + LGE p-value Maron MS et al. 11 7 4 Mayo Clinic 10 10 0 Combined 21 17 4 0.5 0.002 0.04 Foci For Ventricular Arrhythmias? VS LV RV

100 90 80 70 60 50 40 30 20 10 0 p<0.001 p=0.001 p=0.01 Any DE No DE p=0.06 % of HCM Patients with Arrhythmia 24-hour Holter Arrhythmia and Presence of DE NSVT Couplet PVC SVT Adabag et. al. JACC 2008; 51:1369 1.00 Presence of DE vs. Events Event-free rate 0.95 0.90 0.85 0.80 DE (+) DE (-) N=202 N = 202 Follow-up: avg 2 years p = 0.5 0 0.5 1 1.5 2 2.5 3 Follow-up Duration (years) Maron MS et. al. Circ HF 2008; 1:184

Survival to Advanced Age in HCM 25 % HCM Patients 20 15 10 5 19% 14% 8% 0 70 years 75 years 80 years 90 years 2% Survival Age DE as the Only Risk Factor A B VS AML LV FW C Maron BJ et. al. AJC 2008; 101:544

Watkins et.al. NEJM 1992; 326:1108-14 Seidman Lab

Relation Between LV Wall Thickness and Sudden Death in 480 HCM Patients Incidence of Sudden Death per 1000 person - years 20 18 16 14 12 10 8 6 4 2 0 P= 0.001 18.2 11.0 7.4 2.6 0 < 15 16-19 20-24 25-29 > 30 Maximal LV Wall Thickness (mm) Spirito et. al. NEJM 2000; 342:1778 but how low is Low Risk?

Bethesda Conference # 36 Classification Sports (#8) Consensus Panels #2 #3 #4 #5 #6 #7 Congenital Valvular #1 #9 #10 #11 #12 Screening / Dx HCM Other C-M MVP Myocarditis Drugs HTN AED CAD Commotio Arrhythmias Legal Preservation of Life Inappropriate Shocks Lead Complications (25%;5%/y) Infection Thrombosis Recalls

Preservation of Life Inappropriate Shocks Lead Complications (25%;5%/y) Infection Thrombosis Recalls Joshua s Implantable Defibrillator Prizm 2 DR Model 1861 (10/4/01) Connector + Backfill tube Short circuit - DF Feedthrough wire Polyimide tubing *Guidant aware 2002 *Did not inform physicians or patients Electronics Battery *Manufacturing changes 1- April 2002 2- November 2002 *Continued to sell units without the changes during 2002 Hermetic Housing

ICD in HCM : Age at Implant No. of Patients 70 60 50 40 30 20 10 0 <10 16-20 26-30 36-40 46-50 56-60 66-70 11-15 21-25 31-35 41-45 51-55 61-65 71-75 >76 Age At Implant (years) Maron, BJ et. al. JAMA 2007;298:405 Circadian Variability for Appropriate ICD Shocks 12 10 No. of Events 8 6 4 Midnight Noon 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Hour of Day Maron, BJ et. al. Heart Rhythm 2009;6:599

Relation between LV Wall Thickness and Sudden Death in 480 Patients Incidence of Sudden Death per 1000 person - years 20 18 16 14 12 10 8 6 4 2 0 P= 0.001 18.2 11.0 7.4 2.6 0 < 15 16-19 20-24 25-29 > 30 Maximal LV Wall Thickness (mm) Spirito et al. NEJM 2000 ICD : HCM vs. CAD CAD HCM Implant age ~65 ~40 Risk period short long Substrate often usually compromised intact Intervention / yr ~30% 5%

2 prevention Cardiac arrest/sustained VT 1 prevention Familial sudden death Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response Massive LVH Highest ICD Potential arbitrators End-stage phase LV apical aneurysm Marked LV outflow obstruction (rest) Extensive delayed enhancement Modifiable Intense competitive sports CAD Alcohol septal ablation (?) Intermediate Lowest Defibrillator Implants Throughout The World (per million population) United States Germany Canada Ireland Denmark Australia Italy Austria Netherlands Belgium Switzerland Norway Finland United Kingdom Sweden France New Zealand Spain Portugal Japan 133 104 102 91 87 86 84 82 77 66 54 46 45 44 41 40 33 27 17 421

ICD in HCM No. Patients: 506 Centers: 42 Sites: U.S.; Italy / W.Europe;Australia Age: 42±17 years Gender: 64% male LV outflow obstruction::26% Follow-up::3.7±2.8 years Max. LV thickness: 23± 7mm Previously Proposed Pharmacological Therapy For Sudden Death Prevention in HCM ß-adrenergic blockers verapamil procainamide quinidine amiodarone no data proarrhythmia (obsolete) efficacy? chronic use (>3y)?

Impact of Outflow Obstruction (> 30mmHg) on Progression to Severe Heart Failure Related Symptoms and Death in 1101 HCM Patients 100 Cumulative survival in NYHA Class I II (%) 80 60 40 20 p=0.0001 RR= 4.4 Nonobstructive Obstructive 0 0 2 4 6 8 10 Years from First Gradient Measurement Maron, MS et. al. NEJM 2003;348:295 Principles Patients have a fundamental right to be fully informed when they are exposed to the risk of death no matter how low that risk may be perceived. Patients---and their physicians---are entitled to full disclosure of product information that may affect an individual s health or safety.

Profiles in Prognosis for HCM Sudden Death Risk Symptom Progression End- Stage AF ICD Sudden Death in Young Athletes Other congenital HD Ion channelopathies Aortic rupture (2%) Sarcoidosis (1%) Dilated C-M (2%) AS (3%) Other (3%) Normal heart (3%) CAD (3%) Tunneled LAD (3%) HCM (36%) MVP (4%) ARVC (4%) Myocarditis (6%) Coronary artery anomalies (17%) Indeterminate LVH - possible HCM (8%)

Septal Myectomy vs. Alcohol Septal Ablation: Appropriate ICD Shocks No. Pts No. Appropriate Shocks % %/Year Surgical myectomy 50 6 12 2.6 Alcohol septal ablation 17 4 24 10.3 4x p p<0.01 Distribution of Disease - Causing Mutations in HCM Cohort MYBPC3 16% No Mutation 62% MYH7 14% MYL2 2% TNNT2 1.5% TNNI3 1% from Van Driest and Ackerman (Mayo); 2004 Multiple mutations 3% TMP 0.5% ACTC 0.3%

Uncommon Diseases 2500 No. Affected / Million 2000 1500 1000 500 0 HCM Cystic Fibrosis Multiple Sclerosis Muscular Dystrophy LQTS Marfan ALS Brugada Ataxia Primary Prevention of Sudden Death in HCM Over-treatment vs. under-treatment Imperfect risk stratification Patient autonomy Perceived liability ICD is more powerful than our present ability to precisely identify all high risk patients

Deaths with ICDs N = 29 (6%) No HCM: 14 Cancer / Sepsis Renal Suicide Accidents CAD HCM: 14 End-stage Embolic stroke HCM Arrhythmia: 1 (ICD malfunction) Clinical Recognition of HCM Acute Event (11%) Sports/Other Screening (4%) w Routine Exam (33%) Symptom Onset (43%) Adabag et.al. AJC 2006;98:1507 Ada Family Screening (13%)

Unpredictability Joshua s Implantable Defibrillator Prizm 2 DR Model 1861 (10/4/01) Connector + Backfill tube Short circuit - DF Feedthrough wire Polyimide tubing *Guidant aware 2002 *Did not inform physicians or patients Electronics Battery *Manufacturing changes 1- April 2002 2- November 2002 *Continued to sell units without the changes during 2002 Hermetic Housing

Obstacles From Industry II 100 99 Sprint Quattro Secure model 6947 98 Percent Lead Survival 97 96 95 94 93 92 P=0.005 Sprint Fidelis model 6949 91 1 234 5 678 9 101112 13 141516 17 181920 21 222324 25 262728 29 303132 33 343536 37 383940 41 424344 45 464748 49 505152 53 545556 57 585960 61 626364 65 90 1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 Implant Months After the Shock?

Clinical Status Post Appropriate ICD Shock I NYHA Class: Initial VT/VF 25 23 1 NYHA Class: At follow-up 25 1 90% II 5 4 4 2 III 2 1 3 Maron, BJ et. al. Heart Rhythm 2009; 6:993 Sudden Death in Young Athletes Other (5%) HC (36%) WPW (2%) Possible HCM* ( 8%) Dilated CM (2%) AS (3%) Aortic Rupture (3%) CAD (3%) LAD Bridge (3%) MVP (4%) ARVC (4%) Ion Channel (4%) Myocarditis (6%) Coronary Anomalies (17%) Maron, BJ et. al. Circulation 2009; 119:1085-1092

One Risk Factor One Risk Factor Patients With Primary Prevention Appropriate Shock Rates/Year 6 5 4 3 2 1 2.0 2.8 2.9 5.0 0 Massive LVH Family SD NSVT (Holter) Syncope