HCM: The Tip Of The Iceberg. HCM Is A Global Disease. Unidentified. 50 countries.all continents. Rural Minnesota N=15,137;16-87 y 0.

Transcription

1 HCM Is A Global Disease 5 countries.all continents CARDIA N=4,111;23-35 y.17% Rural Minnesota N=15,137;16-87 y.19% Japan N=3,354;2-77 y.17% Amer Indians N=3,51;51-77 y.2% General Population 1:5 6, people in U.S. China N=8,8;18-74 y.16% Tanzania N=6,68;22-91 y.2% AT RISK: 5, 1,? HCM: The Tip Of The Iceberg Identified? Unidentified

2 Clinical Recognition of HCM Sports/Other Screening (4%) Acute Event (11%) w Routine Exam (33%) Symptom Onset (43%) Adabag et.al. AJC 26;98:157 Family Screening (13%) Heterogeneity Asymmetrical hypertrophic cardiomyopathy Asymmetrical hypertrophy of the heart Asymmetrical septal hypertrophy Brock s disease Diffuse muscular subaortic stenosis Diffuse subvalvular aortic stenosis Dynamic hypertrophic subaortic stenosis Dynamic muscular subaortic stenosis Familial hypertrophic subaortic stenosis Familial hypertrophic cardiomyopathy Familial muscular subaortic stenosis Familial myocardial disease Functional aortic stenosis Functional hypertrophic subaortic stenosis Functional obstructive cardiomyopathy Functional obstruction of the left ventricle Functional obstructive subvalvular aortic stenosis Obstructive cardiomyopathy Functional subaortic stenosis Obstructive hypertrophic aortic stenosis Hereditary cardiovascular dysplasia Obstructive hypertrophic cardiomyopathy HYPERTROPHIC CARDIOMYOPATHY (HCM) Obstructive hypertrophic myocardiopathy Hypertrophic constrictive cardiomyopathy Obstructive myocardiopathy ) Hypertrophic hyperkinetic cardiomyopathy Pseudoaortic stenosis Hypertrophic infundibular aortic stenosis Stenosing hypertrophy of the left ventricle Hypertrophic nonobstructive cardiomyopathy Stenosis of the ejection chamber of LV Hypertrophic obstructive cardiomyopathy (HOCM) Subaortic hypertrophic stenosis Hypertrophic stenosing cardiomyopathy Hypertrophic subaortic stenosis Idiopathic hypertrophic subvalvular stenosis Idiopathic muscular hypertrophic subaortic stenosis Idiopathic muscular stenosis of the left ventricle Idiopathic myocardial hypertrophy Idiopathic stenosis of the flushing chamber of LV Idiopathic ventricular septal hypertrophy Irregular hypertrophic cardiomyopathy Left ventricular muscular stenosis Low subvalvular aortic stenosis Muscular aortic stenosis Muscular hypertrophic stenosis of LV Muscular stenosis of the left ventricle Muscular subaortic stenosis Muscular subvalvular aortic stenosis Non-dilated cardiomyopathy Nonobstructive hypertrophic cardiomyopathy Subaortic idiopathic stenosis Subaortic muscular stenosis

3 27 yr/old female Genotyped based on +FH (MyBPC)/ Phenotype (-) 33 yr/old now and development of LVH and SAM; Phenotype (+) Age 27y Age 33y Maron, BJ et. al. JACC 21;38:315

4 A Echo B CMR RV VS LV * * * RV VS LV Hypertrophic Cardiomyopathy Sarcomeric Protein Mutations Non-Sarcomeric Mutations ~ 11 Genes--- or more? > 1 mutations AMP-Kinase (PRKAG2) Lamp2 (Danon) Storage Diseases Fabry Disease

5 A B Ao VS LVFW C D Survival with HCM in an Unselected Cohort of Adults (Diagnosis > age 2) Cumulative Survival Rate n=234 Avg. follow-up=8.1 years HCM mortality rate=1.2%/yr p=.22 HCM U.S. National Health Statistics Maron BJ et al. JAMA 28 Duration from Initial Diagnosis (years)

6 HCM: A Bad Disease? Or a Disease That Can Be Bad? Profiles in Prognosis for HCM Sudden Death Risk Symptom Progression End- Stage AF

7 Arrhythmogenic Myocardial Substrate in HCM % HCM Mortality Per Age Group Sudden Stroke Heart Failure >75 Age at Death or Most Recent Evaluation (years) Maron, BJ et. al. Circulation 2;12:858 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 29; 119:

8 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. HCM: identification of high risk patients? 1. DE vs. Events Event-free rate DE (+) DE (-) N=22 N = 22 Follow-up: days p = Follow-up Duration (years)

9 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 Relation Between LV Thickness & SCD in 482 HCM Patients % Patients With SCD < Max. LV Wall Thickness (mm)

10 A P VS D B P D C Figure 1. VS D P LA D E F * * * * * * Patients with LVAA (n=28) 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 Foci For Ventricular Arrhythmias? VS LV RV

11 % of HCM Patients with Arrhythmia hour Holter Arrhythmia and DE p<.1 p=.1 p=.1 Any DE No DE p=.6 NSVT Couplet PVC SVT DE as the Only Risk Factor A B VS AML LV FW C Prevention of Sudden Death In HCM

12 Drugs Do Not Protect Absolutely From Sudden Death In HCM 3 27% % On Drug w/ Sudden Death % 17% 2% Amio Verapamil Beta- Blocker Disopyramide N Engl J Med 198;33: y Brother SD 36 y ICD 5 y: 9 y: 4 y Generator replaced 41 y Appropriate shock #1 5 y Appropriate shock #2 52y Present

13 HCM is Unpredictable 12 Circadian Variability for Appropriate ICD Shocks 1 No. of Events Midnight Noon Hour of Day Maron, BJ et. al. Heart Rhythm 29;6:599 ICD in HCM : Age at Implant No. of Patients < > Age At Implant (years) Maron, BJ et. al. JAMA 27;298:4

14 ICD in HCM: Follow-up = 3.7 ± 3 years 13 Appropriate Shocks VT/VF (2%) 5.5%/ yr ICD discharge rate 11% 4% 2º prevention 1º prevention Maron, BJ et. al. JAMA 27;298:4 High-Risk Children with HCM and ICDs Implanted < 2 years: Appropriate shocks: Age at intervention: Implanted < 15 years: Appropriate shocks: Age at intervention: (28%;7%/y) years (35%;11%/y) years Rate of Appropriate Shocks (1 person-yr) % of appropriate shocks Overall p= No. Risk Factors for Primary Prevention Maron, BJ et. al. JAMA 27;298:4

15 One Risk Factor Patients With Primary Prevention Appropriate Shock Rates/Year Massive LVH Family SD NSVT Syncope (Holter) Maron, BJ et. al. JAMA 27;298:4 No. Patients ICD in HCM - II: Time to First Shock Duration (months) >9 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 27;298:4

16 After the Shock? Trading SD for CHF Moss et. al. MADIT-II Circulation 24 11: Clinical Status Post Appropriate ICD Shock NYHA Class: Initial VT/VF NYHA Class: At follow-up I % II III Maron, BJ et. al. Heart Rhythm 29; 6:993

17 Primary Prevention Decision Tree: ICD In HCM Risk Factors High--? risk Some risk Cardiologist TRANSPARENCY / FULL DISCLOSURE / INFORMED CONSENT Patient Autonomy 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 Profiles in Prognosis for HCM Sudden Death Risk Symptom Progression End- Stage AF

18 Management of HCM? Asymptomatic? Verapamil Mild-Moderate Symptoms Verapamil Beta-blocker + Diuretic Severe Symptoms Treatment Failure Refractory Severe Symptoms Verapamil + Diuretic Disopyramide Diltiazem Beta-blocker + Verapamil Subaortic Obstruction Alcohol DDD Septal Pacing Ablation Septal Myotomy-Myectomy Myectomy Nonobstructive Heart Transplantation Impact of Outflow Obstruction (> 3mmHg) on Progression to Severe Heart Failure - Related Symptoms and Death in 111 HCM Patients 1 Cumulative survival in NYHA Class I-II (%) p=.1 RR= Nonobstructive Obstructive Years from First Gradient Measurement Maron,MS NEJM 23:348:295 LV Outflow Gradient (mmhg) Maron, MS, MS, Circulation, in press in press Maron MS,, in Circulation, press MS, Circulatio in press Ө Rest Ө Betablocker Betablocker Post- Exercise

19 Case for Septal Myectomy: The Gold Standard 45 years of experience Low operative mortality ( 1%) & virtually zero last 1 major centers) --- lower than ablation Permanent, virtually complete reduction LVOTG to -1mmHg 85%: substantial reduction heart failure over long time Anatomic flexibility, under direct visualization Permits revision mitral / submitral anomalies No residual no septal scar Monitor / revise resection w/ intraoperative echo Rapid reduction of obstruction Evidence of increased survival, possibly normal longevity Surgical Septal Myectomy 1..9 Survival Isolated Myectomy Nonoperated obstructive Expected ---US population P<.1 83% 61% Years Post-op Ommen, S et. al. JACC 26 Septal Ablation: HCM

20 Major Issues with Alcohol Septal Ablation Short follow-up: Is gradient / symptom relief longlasting? Residuals common ie. PMK and ICD (2%) Relatively high rate of repeat procedures (25%) Often not successful w/ high gradients Dobutamine contamination of gradient data Myectomy after failed ablations is difficult The infarct/ scar and SD risk, particularly in the young Septal Scarring Post-ablation Post-myectomy Septal Scar VS=3% LV1% No Scar Valeti et. al. JACC 27;49:35

21 Ventricular Tachyarrhythmias and Sudden Death Following Alcohol Septal Ablation % Patients With Sustained VT/VF/SD % 7% 1% 24% 25% Sorajja Cuoco Noseberry Maron van der Lee Benign/Stable (normal longevity) Profiles in Prognosis for HCM Sudden Death Progressive Heart Failure End- Stage AF & Stroke Clinical Pathways of Prognosis in HCM Normal Longevity SD Progressive HF End Stage AF & Stroke ICD Drugs Myectomy (alcohol ablation) Transplant Drugs warfarin RFA

22 Benign/Stable (normal longevity) Profiles in Prognosis for HCM Sudden Death Risk Symptom Progression End Stage AF ICD The Uncommon Diseases 25 No. Affected / Million HCM Cystic Fibrosis Multiple Sclerosis Muscular Dystrophy LQTS Marfan ALS Brugada Ataxia

23 Women With HCM Diagnosed less frequently Older when diagnosed (implying delay) More symptomatic when diagnosed Later recognition of symptoms More commonly have outflow obstruction Olivotto et. al. JACC 25;46:48 HCM and Race African- American (8%) White (45%) African- American (55%) White (92%) Competitive Athletes: HCM-related Sudden Death (n=12) Hospital Based HCM Patients (n=1,986)

24 Bethesda Conference # 36 Classification Sports (#8) Consensus Panels #2 #3 #4 #5 #6 #7 Congenital Valvular #1 #9 #1 #11 #12 Screening / Dx HCM Other C-M MVP Myocarditis Drugs HTN AED CAD Commotio Arrhythmias Legal HCM is a Predominantly Obstructive Disease Non-Obstructive (95; 3%) Rest Obstruction (119; 37%) Provokable Obstruction (Exercise) (16; 33%) 7% 39 Survived Cardiac Arrest ICD Shock Died 7 SCD (1) End-stage (4) Non-HCM (2) No recurrence 32 Recurrent cardiac arrest/ ICD shock y (up to 3 y) y Maron, BJ et. al. Heart Rhythm 29 6:

25 ICD in HCM No. Patients: 56 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 ICD : HCM vs. CAD CAD HCM Implant age ~65 ~4 Risk period short long Substrate often usually compromised intact Intervention / yr ~3% 5% Deaths N = 29 (6%) No HCM: 14 cancer / sepsis renal suicide accidents CAD HCM: 14 End-stage Embolic stroke HCM Arrhythmia: 1 (ICD malfunction)

26 Short and Long-Term Outcome After Alcohol Septal Ablation for Obstructive HCM (91 patients) n=9 Deaths n=7 n=7 Aborted SD Failed Procedure n=4 n=4 App. ICD Shocks PMK n=2 MI about one-third of HCM patients who underwent alcohol septal ablation developed one or more cardiovascular complications over 5.6 years tencate et. al. Thoraxcentrum Rotterdam, The Netherlands Impact of Outflow Obstruction (> 3mmHg) on Risk For Sudden Death in 111 HCM Patients Cumulative Survival (%) p<.2 Nonobstructive Obstructive Years from First Gradient Measurement Other Possible Contributing Risk Factors In Individual HCM Patients AF Myocardial ischemia Bridged LAD Alcohol Septal Ablation LV outflow obstruction

27 Clinical Implications of LAMP2 Cardiomyopathy Survival after age 25 years unlikely Requires molecular diagnosis Deserves consideration for heart transplantation Strongest Risk Factors: Cardiac arrest Familial SD Syncope Multiple-repetitive NSVT BP exercise Massive LVH End-Stage Apical aneurysm Malignant genotype (?) Alcohol Ablation (?) Highest Intermediate ICD Lowest Septal Myectomy vs. Alcohol Septal Ablation: Appropriate ICD Shocks No. Pts No. Appropriate Shocks % %/Year Surgical myectomy Alcohol septal ablation x p p<.1

28 One Risk Factor Patients With Primary Prevention Appropriate Shock Rates/Year Massive LVH Family SD NSVT (Holter) Syncope Joshua s Implantable Defibrillator Prizm 2 DR Model 1861 (1/4/1) + Backfill tube Short circuit Connector - DF Feedthrough wire Polyimide tubing *Guidant aware 22 *Did not inform physicians or patients Electronics Battery *Manufacturing changes 1- April November 22 *Continued to sell units without the changes during 22 Hermetic Housing

29 Resting LVOT Gradient, mmhg NS P <.1 Ablation Myectomy P <.1 2 Before Intervention Immediately After Follow-up Qin JX, et al. JACC 21;38: A. B. C. VS D. E. F. VS LV RV HCM: A Bad Disease? Or a Disease That Can Be Bad?

30 35 y Brother SD (age 39) 5 y: 9 y: 36 y ICD 4 y Generator replaced 41 y Appropriate shock #1 5 y Appropriate shock #2 HCM Is A Global Disease Previously Proposed Pharmacologic Therapy For Sudden Death Prevention in HCM ß-adrenergic blockers verapamil procainamide quinidine amiodarone no data proarrhythmia (obsolete) efficacy? chronic use (>3y)?

31 HCM Cohorts Annual Mortality Tertiary referral based Children 4 6 % Children & adults 3 4 % Community based % non tertiary regional unselected Non-dilated Dilated

32 End-Stage EF < 5% LV Cavity LV Wall Surgery Ablation 14% Serruys et al. Circulation 25; 112: 482 Rotterdam Thorax Ctr. 12 % of Patients % 9% 5% 9% 4 3% 2 2% Death Acute MI VF PMR ICD Re- Intervention

33 Peak O 2 consumption (ml/kg/min) P < Pre Post Pre Post Myectomy Ablation Firoozi et al. Eur Heart J 22;23:1617. Japan N=3,354;2-77 y.17% CARDIA N=4,111; y.17% Rural Minnesota N=15,137; y.19% Amer Indians N=3,51;51-77 y.2% General Population 1:5 China N=8,8; y.16% 5, people in U.S. AT RISK: 5, 1,?

34 The Uncommon Diseases 25 No. Affected / Million HCM Cystic Fibrosis Multiple Sclerosis Muscular Dystrophy LQTS Marfan ALS Brugada Ataxia Sudden Death in Young Athletes Other congenital HD Ion channelopathies Aortic rupture (2%) Sarcoidosis (1%) Dilated C-M (2%) AS (3%) CAD (3%) Tunneled LAD (3%) MVP (4%) ARVC (4%) Other (3%) Normal heart (3%) Myocarditis (6%) Coronary artery anomalies (17%) HCM (36%) Indeterminate LVH - possible HCM (8%)

35 Genetically affected w /o phenotype HCM Population Longitudinal follow-up No / mild symptoms (low SD risk) No Rx Drugs* Non-obstructive (rest & provocation) Heart failure symptoms Drugs* Refractory congestive symptoms AF High risk SD Obstructive (rest & / or provocation) ICD Rate-control; Cardioversion; Anti-coagulation Heart transplant for end-stage Surgery: myectomy DDD pacing Surgical alternatives Alcohol septal ablation Bethesda Conference # 26 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. Asymmetrical hypertrophic cardiomyopathy Asymmetrical hypertrophy of the heart Asymmetrical septal hypertrophy Brock s disease Diffuse muscular subaortic stenosis Diffuse subvalvular aortic stenosis Dynamic hypertrophic subaortic stenosis Dynamic muscular subaortic stenosis Familial hypertrophic subaortic stenosis Familial hypertrophic cardiomyopathy Familial muscular subaortic stenosis Familial myocardial disease Functional aortic stenosis Functional hypertrophic subaortic stenosis Functional obstructive cardiomyopathy Functional obstruction of the left ventricle Functional obstructive subvalvular aortic stenosis Functional subaortic stenosis Hereditary cardiovascular dysplasia HYPERTROPHIC CARDIOMYOPATHY (HCM) Hypertrophic constrictive cardiomyopathy Hypertrophic hyperkinetic cardiomyopathy Hypertrophic infundibular aortic stenosis Hypertrophic nonobstructive cardiomyopathy Hypertrophic obstructive cardiomyopathy (HOCM) Hypertrophic stenosing cardiomyopathy Hypertrophic subaortic stenosis Idiopathic hypertrophic cardiomyopathy Idiopathic hypertrophic obstructive cardiomyopathy Idiopathic hypertrophic subaortic stenosis (IHSS) Idiopathic hypertrophic subvalvular stenosis Idiopathic muscular hypertrophic subaortic stenosis Idiopathic muscular stenosis of the left ventricle Idiopathic myocardial hypertrophy Idiopathic stenosis of the flushing chamber of LV Idiopathic ventricular septal hypertrophy Irregular hypertrophic cardiomyopathy Left ventricular muscular stenosis Low subvalvular aortic stenosis Muscular aortic stenosis Muscular hypertrophic stenosis of LV Muscular stenosis of the left ventricle Muscular subaortic stenosis Muscular subvalvular aortic stenosis Non-dilated cardiomyopathy Nonobstructive hypertrophic cardiomyopathy Obstructive cardiomyopathy Obstructive hypertrophic aortic stenosis Obstructive hypertrophic cardiomyopathy Obstructive hypertrophic myocardiopathy Obstructive myocardiopathy Pseudoaortic stenosis Stenosing hypertrophy of the left ventricle Stenosis of the ejection chamber of LV Subaortic hypertrophic stenosis Subaortic idiopathic stenosis Subaortic muscular stenosis Subvalvular aortic stenosis of the muscular type Teare s disease

36 % Myocardium with DE p< Ejection Fraction (%) Bypass Angioplasty Revascularization Investigation (BARI) Theoretical Surgical Myectomy vs. Alcohol Septal Ablation Trial 25,2 Patients Undergoing Coronary Angiogram 34, HCM Patients to be Screened 12,53 (5%) 4,11 1,829 (7%) Clinically Eligible 67% Exclusion Criteria 55% Eligible for Both CABG and PTCA Refused Randomization Enrolled and Randomized 3,4 (1%) 2,4 Clinically Eligible: Obstruction & Severe Refractory Symptoms ~3% Exclusion Criteria ~ 5% Eligible for Both Myectomy and ASA Refuse Randomization 1,2 (3.5%) Enrolled and Randomized CABG PTCA Myectomy ASA 6 6

37 Profiles in Prognosis for HCM Sudden Death Risk Symptom Progression End- Stage AF ICD 8 Age at Death (years) Sudden Heart Failure Stroke Mode of HCM Death Hypertrophic Cardiomyopathy Sarcomeric Protein Mutations Non-Sarcomeric Mutations ~ 11 Genes--- or more? > 4 mutations AMP-Kinase (PRKAG2) Lamp2 (Danon) Storage Diseases Fabry Disease

38 Case for Septal Myectomy: The Gold Standard 45 years of experience Permanent, virtually complete reduction LVOTG to -1mmHg 85%: substantial reduction heart failure over long time Permits revision mitral / submitral anomalies Monitor / revise resection w/ intraoperative echo Rapid reduction of obstruction Evidence of increased survival, possibly normal longevity Its All About Patient Selection Myectomy Primary option Particularly, for younger patients w/ substantial life expectancy Ablation Alternative option Particularly, poor operative candidates significant co-morbidity advanced age reject surgery

39 7 p <.1 Ablation Myectomy Ralph-Edwards et al. J Thorac CV Surg 25; 129: % 5 p <.1 % of Patients % p <.1 15% 5% 42% 14% p <.1 6% p <.1 12% NYHA III/IV Post-Op Rest Gradient Post-Op Provocable Gradient % Late CV Death % Failure Surgery Ablation Time 45 years 5 yr Cases ~ 3, > 3,5 Ablation > Surgery by 1-35x in last 5 years A B Ao VS LVFW C D

40 Case for Septal Myectomy: The Gold Standard 45 years of experience Permanent, virtually complete reduction LVOTG to -1mmHg 9%: substantial reduction heart failure over long time Permits revision mitral / submitral anomalies Monitor / revise resection w/ intraoperative echo Rapid reduction of obstruction Low operative mortality ( 1%) & virtually zero last 12 major centers) --- lower than ablation 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. Impact of Outflow Obstruction (> 3mmHg) on Risk For Sudden Death in 111 HCM Patients Cumulative Survival (%) p<.2 Nonobstructive Obstructive Years from First Gradient Measurement

41 Consecutive Pure Myectomy Patients w/o An Operative Death Mayo Clinic Cleveland Clinic Toronto General Total 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); 24 TMP.5% ACTC.3% Multiple mutations 3%

42 Obstacles From Industry 1 99 Sprint Quattro Secure model Percent Lead Survival P=.5 Sprint Fidelis model Implant Months Major Issues with Alcohol Septal Ablation Short follow-up: Is gradient / symptom relief long-lasting? Residuals common ie. PMK and ICD (2%) Relatively high rate of repeat procedures (25%) Often not successful w/ high gradients Myectomy after failed ablations is difficult Anatomic inflexibility perforator distribution

43 HCM DISEASE SPECTRUM Marked Outflow Obstruction + Severe Symptoms (5%) ICD in HCM: Age at Implant 25 No. of Patients < >76 Age At Implant (years) Major Issues: Alcohol Septal Ablation Short follow-up: Is gradient / symptom relief longlasting? Residuals common ie. PMK and ICD (2%) Anatomic inflexibility perforator distribution / selection Relatively high rate of repeat procedures (25%) Often not successful w/ high gradients Dobutamine contamination of gradient data Myectomy after failed ablations is difficult The infarct/ scar and SD risk, particularly in the young

44 Genetically affected w /o phenotype HCM Population Longitudinal follow-up No / mild symptoms (low SD risk) No Rx Drugs* Non-obstructive (rest & provocation) Heart failure symptoms Drugs* Refractory congestive symptoms AF High risk SD Obstructive (rest & / or provocation) ICD Rate-control; Cardioversion; Anti-coagulation Heart transplant for end-stage Surgery: Myotomy-myectomy DDD pacing Surgical alternatives Alcohol septal ablation Relationship of Massive LVH to Age in HCM % Patients in Age Groups With Max. LV>3mm >7 Age at Initial Evaluation Max. LV = 3-34mm Max. LV 35mm Primary Prevention of SD in HC 1 or 2 risk factors required? ---Individualization--- Over-treatment vs. under-treatment Imperfect risk stratification Perceived liability ICD is more powerful than our present ability to precisely identify all high risk patients

45 Surgery Ablation Time 45 years 5 yr Cases ~ 3, > 3,5 Ablation > Surgery by 1-35x in last 5 years Myectomy Enhances Long-term Survival 1. Overall Survival p=.1 Myectomy Expected ---U.S. population Nonoperated obstructive 83% 61% Years Post-op LV Outflow Gradient (mmhg) Maron, MS, MS, Circulation, in press in in press press Maron MS,, in Circulation, press MS, Circulatio in press Ө Rest Ө Post- Exercise

46 Family Screening Strategies to Detect HC With Echo / ECG (Absent Genetic Testing) < 12 years old optional unless: malignant family competitive athlete suspicion of early onset LVH 12 to 18 years old q mo. > 18 years old q every 5 years (or until routine genetic testing available to resolve) Glycogen Storage Cardiomyopathies (mimic HCM) PRKAG2 (AMP-kinase) Ventricular pre-excitation (in some) Range in age (31 ± 15 y) Relatively mild LVH Cardiac Danon (Lamp 2) Ventricular pre-excitation (often) Young males < 25 y Massive LVH (35 ± 15 mm) Tall ECG voltages Abnormal chemistries ALT / CPK

47 HCM Cohorts Annual Mortality Tertiary referral based Children 4 6 % Children & adults 3 4 % Community based % non tertiary regional unselected Barry J. Maron, MD Interventions for Obstructive HCM Minneapolis (14years) No. HCM Patients 958 Referrals for surgical myectomy 114 (12%) Referred for alcohol ablation 14 (1%) Total Interventions (~ 9 pts / yr) 128 (13%)

48 Non-Obstructive (95; 3%) Rest Obstruction (119; 37%) Provokable Obstruction (Exercise) (16; 33%) 7% Maron MS, Circulation,in press Survival With HCM According to Age at Diagnosis 12 1 Percent Survival HCM 5 yr Gen. Pop. Gen. Pop. HCM < 5 yr P=.1 P= Years From HCM Diagnosis

49 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 device therapy) Risk factors cannot be summed numerically ICD decisions may also be based on individualphysicianjudgment/patient autonomy considerations Barry J. Maron, MD Interventions for Obstructive HC Minneapolis (1 years) No. HC Patients 725 Referrals for surgical myectomy 2 (2.8%) Referred for alcohol ablation 5 (.7%) Total Interventions (~ 2 pts / yr) 25 (3.5%) ICD in HCM No. Patients: 56 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

50 ICD : HCM vs. CAD CAD HCM Implant age ~65 ~4 Risk period short long Substrate often usually compromised intact Intervention / yr ~3% 7% The Oukrop Family ICD: 1/4/1 25 The Uncommon Diseases No. Affected / Million HCM Cystic Fibrosis Multiple Sclerosis Muscular Dystrophy LQTS Marfan ALS Brugada Ataxia

51 Asymmetrical hypertrophic cardiomyopathy Asymmetrical hypertrophy of the heart Asymmetrical septal hypertrophy (ASH) Brock s disease Diffuse muscular subaortic stenosis Diffuse subvalvular aortic stenosis Dynamic hypertrophic subaortic stenosis Dynamic muscular subaortic stenosis Familial hypertrophic subaortic stenosis Familial hypertrophic cardiomyopathy (FHC) Familial muscular subaortic stenosis Familial myocardial disease Functional aortic stenosis Functional hypertrophic subaortic stenosis Functional obstructive cardiomyopathy Functional obstruction of the left ventricle Functional obstructive subvalvular aortic stenosis Functional subaortic stenosis Hereditary cardiovascular dysplasia HYPERTROPHIC CARDIOMYOPATHY (HCM) Hypertrophic constrictive cardiomyopathy Hypertrophic hyperkinetic cardiomyopathy Hypertrophic infundibular aortic stenosis Hypertrophic nonobstructive cardiomyopathy Hypertrophic obstructive cardiomyopathy (HOCM) Hypertrophic stenosing cardiomyopathy Hypertrophic subaortic stenosis Idiopathic hypertrophic cardiomyopathy Idiopathic hypertrophic obstructive cardiomyopathy Idiopathic hypertrophic subaortic stenosis (IHSS) Idiopathic hypertrophic subvalvular stenosis Idiopathic muscular hypertrophic subaortic stenos Idiopathic muscular stenosis of the left ventricle Idiopathic myocardial hypertrophy Idiopathic stenosis of the flushing chamber of LV Idiopathic ventricular septal hypertrophy Irregular hypertrophic cardiomyopathy Left ventricular muscular stenosis Low subvalvular aortic stenosis Muscular aortic stenosis Muscular hypertrophic stenosis of LV Muscular stenosis of the left ventricle Muscular subaortic stenosis (MSS) Muscular subvalvular aortic stenosis Non-dilated cardiomyopathy Nonobstructive hypertrophic cardiomyopathy Obstructive cardiomyopathy Obstructive hypertrophic aortic stenosis Obstructive hypertrophic cardiomyopathy Obstructive hypertrophic myocardiopathy Obstructive myocardiopathy Pseudoaortic stenosis Stenosing hypertrophy of the left ventricle Stenosis of the ejection chamber of LV Subaortic hypertrophic stenosis Subaortic idiopathic stenosis Subaortic muscular stenosis Subvalvular aortic stenosis of the muscular type Teare s disease LV Outflow Gradient (mmhg) Maron, MS, MS, Circulation, in press in in press press Maron MS,, in Circulation, press MS, Circulatio in press Ө Rest Ө Post- Exercise Non-Obstructive (95; 3%) Rest Obstruction (119; 37%) Provokable Obstruction (Exercise) (16; 33%) 7% Maron MS, Circulation,in press

52 Other Possible Contributing Risk Factors In Individual HCM Patients AF Myocardial ischemia Bridged LAD Alcohol Septal Ablation LV outflow obstruction RV vs LV vs RV LV NYHA III; EF 4%; 3% DE NYHA I; EF 65%; 46% DE

53 Subsequent Events June: Guidant recalled 26, Prizm 2 DR ICDs. June: Guidant recalled 16, Contak ICDs after a patient died due to a short-circuit problem the company had identified a year earlier. June: Guidant recalled 21, AVT ICDs. June: Guidant recalled 46, Renewal ICDs. July: Guidant recalled 28, pacemakers that were prone to abrupt failure and runaway pacing that caused at least one death. > 18, devices Late Onset LVH 3 % Myocardium with DE p< Ejection Fraction (%)

54 HCM and Race African- American (5%) White (45%) African- American (55%) White (92%) Competitive Athletes: HCM-related Sudden Death (n=12) Hospital Based HCM Patients (n=1,986) Commercial Diagnostic Genetic Testing for HCM Laboratory of Molecular Medicine (Partner s Health Care; Harvard Medical School) Tests for known and novel mutations in 1 most common HCM genes 7 cc blood Results: 4 weeks Cost: $28; $2 / each relative Limitations: - cost - false negatives High-Risk Children with HCM and ICDs Implanted < 2 years: Appropriate shocks: Age at intervention: Implanted < 15 years: Appropriate shocks: Age at intervention: (28%;7%/y) years (35%;11%/y) years

55 Case for Septal Myectomy: The Gold Standard 45 years of experience Low operative mortality ( 1%) & virtually zero last 12 major centers) --- lower than ablation Permanent, virtually complete reduction LVOTG to -1mmHg 85%: substantial reduction heart failure over long time Anatomic flexibility, under direct visualization Permits revision mitral / submitral anomalies No residual no septal scar Monitor / revise resection w/ intraoperative echo Rapid reduction of obstruction Evidence of increased survival, possibly normal longevity Septal Myectomy vs. Alcohol Septal Ablation: Appropriate ICD Shocks No. Pts No. Appropriate Shocks % %/Year Surgical myectomy Alcohol septal ablation x p p<.1 Other Possible Contributing Risk Factors In Individual HCM Patients AF Myocardial ischemia Bridged LAD Alcohol Septal Ablation LV outflow obstruction

56 Septal Scarring Post-ablation Post-myectomy Septal Scar VS=3% LV1% No Scar Septal Myectomy vs. Alcohol Septal Ablation: Appropriate ICD Shocks No. Pts No. Appropriate Shocks % %/Year Surgical myectomy Alcohol septal ablation x p p<.1

57 Bethesda Conference # 36 Classification Sports (#8) Consensus Panels #2 #3 #4 #5 #6 #7 Congenital Valvular #1 #9 #1 #11 #12 Screening / Dx HCM Other C-M MVP Myocarditis Drugs HTN AED CAD Commotio Arrhythmias Legal CMR Delayed Enhancement? Clinical Recognition of HCM Acute Event (11%) w Sports/Other Screening (4%) Routine Exam (33%) Symptom Onset (43%) Family Screening (13%)

58 A B VS AML LV FW C A B B Ao LA RV VS FW C D LA VS LV E * VS LV RV

59 Minnesota 243 (88%) Minneapolis-St. Paul 83 (3%) N. N. Dakota, S. S. Dakota, Iowa, Wisconsin (12%) Defibrillator Implants Throughout The World - 23 (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 Drugs Do Not Protect Absolutely From Sudden Death In HCM 3 27% % On Drug w/ Sudden Death % 17% 2% Amio Verapamil Beta- Blocker Disopyramide

60 1416 g 65 mm A B C D