Barry J. Maron, MD Hypertrophic Cardiomyopathy Institute Tufts Medical Center Boston, MA. Disclosures: Medtronic (Grantee) GeneDx (Consultant)

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1 How Hypertrophic Cardiomyopathy Became a Contemporary Treatable Genetic Disease With Low Mortality Shaped by 50 Years of Clinical Research and Practice Barry J. Maron, MD Hypertrophic Cardiomyopathy Institute Tufts Medical Center Boston, MA Disclosures: Medtronic (Grantee) GeneDx (Consultant)

2 First Principle: HCM is a disease compatible with normal longevity without disability or need for intervention

3 % of Patients Major Adverse Disease Pathways in HCM 60 56% % % 8% 0 Major Treatment End-Point Pathways

4 Benign/Stable (normal longevity) Profiles in Prognosis for HCM Sudden Death Progressive Heart Failure End- Stage AF & Stroke

5 U.S./Canada: ACC/AHA: prevention Cardiac arrest/sustained VT 1 prevention Family history HCM-SD Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response LGE 15% of LV mass Massive LVH 30 mm Rare subgroups/potential arbitrators End-stage (EF < 50%) LV apical aneurysm Marked LV outflow obstruction (rest) Modifiable Intense competitive sports CAD LGE 15% of LV mass Age 60y Alcohol septal ablation (?) Highest Intermediate Lowest ICD

6 % Patients With SCD Relation Between LV Thickness & SCD in 482 HCM Patients < Max. LV Wall Thickness (mm)

7 Echo CMR A B RV VS LV * * * RV VS LV

8 U.S./Canada: ACC/AHA prevention Cardiac arrest/sustained VT 1 prevention Family history HCM-SD Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response LGE 15% of LV mass Massive LVH 30 mm Rare subgroups/potential arbitrators End-stage (EF < 50%) LV apical aneurysm Marked LV outflow obstruction (rest) Modifiable Intense competitive sports CAD LGE 15% of LV mass Age 60y Alcohol septal ablation (?) Highest Intermediate Lowest ICD

9 % of HCM Cohort Outcome of HCM Patients First Evaluated 60 Years % Aging is Good in HCM % 12% 0.2%/y 0 Maron BJ et. al. Circ 2013; 127: 585 Alive Non- Cardiac Death Non-HCM Cardiac Death 2% 1% 1% Embolic Stroke Heart Failure HCM Death SCD

10 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 0.5%/year

11 U.S./ Canada (ACC/AHA) prevention Cardiac arrest/sustained VT 1 prevention Family history HCM-SD Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response LGE 15% of LV mass Massive LVH 30 mm Rare subgroups/potential arbitrators End-stage (EF < 50%) LV apical aneurysm Marked LV outflow obstruction (rest) Modifiable Intense competitive sports CAD LGE 15% of LV mass Age 60y Alcohol septal ablation (?) Highest Intermediate Lowest ICD

12 A P VS D B P D C VS P Figure 1. D LA D E F * * * * * *

13 HCM with Apical Aneurysm and Scar

14 Survival free from HCM related mortality and adverse events HCM Related Death or Adverse Clinical Events in 93 Patients with LV Apical Aneurysms %/year 0.6 Log-rank test p< %/year 0.2 HCM patients without LV apical aneurysms HCM patients with LV apical aneurysm Years from First Evaluation

15 A B C VS LV VS RV Prevalence of LGE = 55-70% D E F LA LA

16 Survival Extent of LGE vs. Sudden Death Risk in HCM LGE LGE L G E LGE (-) LGE < 10% LGE 10-20% LGE > 20% Follow-up (years) Chan RH et. al. Circ 2014; 130(6):

17 2 prevention Cardiac arrest/sustained VT 1 prevention Family history HCM-SD Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response LGE 15% of LV mass Massive LVH 30 mm Rare subgroups/potential arbitrators End-stage (EF < 50%) LV apical aneurysm Marked LV outflow obstruction (rest) Modifiable Intense competitive sports CAD LGE 15% of LV mass Age 60y Alcohol septal ablation (?) Highest Intermediate Lowest ICD

18 Prevention of Sudden Death in HCM

19 ICD Performance in HCM 506 Follow-up = 3.7 ± 3 years 103 Appropriate Shocks (20%) VT/VF 5.5%/y ICD discharge rate 11%/y 4%/y 2º prevention 1º prevention Maron BJ et. al. JAMA 2007; 298:

20 Rate of Appropriate Interventions per 100 person-yr Appropriate Shocks (35%) Overall p= No. of Risk Factors for Primary Prevention

21 Primary Prevention Decision Tree: ICD In HCM Risk Factors High risk? Some risk Cardiologist TRANSPARENCY / FULL DISCLOSURE / INFORMED CONSENT Patient Autonomy

22 NEW PARADIGM IN HYPERTROPHIC CARDIOMYOPATHY

23 Evidence for Decreased HCM Mortality: 2000 Patients Presenting years Old Tufts Medical Center What is Possible..and Role of HCM Centers

24 % Death Per Year Maron BJ et. al. JACC in press 1.4 Pre-ICD era 1.5%/y %/y 86 ICD interventions General Population "Historic Mortality"

25 % Death Per Year %/y 0.8%/y General Population "Historic Mortality"

26 % Death Per Year %/y 0.8%/y 45 Transplants 0.0 General Population "Historic Mortality"

27 % Death Per Year %/y %/y General Population "Historic Mortality"

28 % Death Per Year %/y 0.6%/y General Population "Historic Mortality" 30 OHCA (w/ hypothermia)

29 % Death Per Year Current Mortality lives saved 0.8%/y p = %/y

30 % Death Per Year %/y Advanced Heart Failure (n = 21) SCD (n = 15) Stroke (n=1) Current Mortality 2014

31 % Death Per Year %/y Advanced Heart Failure (n = 21) SCD (n = 15) Stroke (n=1) Current Mortality SCDs but 5 declined ICD 7 pre-icd era

32 HCM-Related Mortality (n = 474) (n = 1000) (n = 428) Age in Years Initial Evaluation

33 Sudden Death Advanced HF

34 Paradigm Change in Causes of Death: Advanced Heart Failure w/o Obstruction (transplant/transplant candidates) (60%) All HCM Patients 3% Current Causes of HCM Mortality (2015)

35 Survival Surgical Myectomy: Quality of Life/Survival Reversal Form of HF % Isolated Myectomy Nonoperated obstructive Expected ---US population P< % Years Post-op Ommen S et. al. JACC 2006

36 Major Surgical Myectomy Centers (North America) Center No. Myectomy Mort. Mayo % Cleveland % Tufts % Toronto % NYU % %

37 WHO SHOULD DO IT? (Operative Mortality) Community Hospitals 8% HCM Centers 0.4%

38 Relation of Progressive Heart Failure to Outflow Obstruction Non- Obstructive Provocable Obstruction Rest Obstruction No. Patients Proportion of patients who developed NYHA class III/IV 10% 90% 20% 80% 38% 62% Rate of Progression to NYHA Class III/IV, (%/y) 1.6%/y 3.2%/y 7.4%/y

39 ITS PROBABLY BETTER TO BE NONOBSTRUCTIVE..UNLESS YOU GET REALLY SICK

40 % HCM Mortality %/y Early HCM Referral Cohorts HCM Cohorts: Prior to utilization of current treatment strategies/ interventions 1 1.5%/y ICD intervention Heart transplant/myectomy OHCA/defibrillation/hypothermia %/y Present HCM Cohort: Contemporary treatment 0.8%/y 0 HCM-Related Mortality General U.S. Population

41 Most HCM Patients Do Not Die of HCM 75% of HCM Patients Die of Other, Most Commonly Non-Cardiac, Conditions Most HCM-Related Deaths occur in Younger Patientsp

42 Benign/Stable (normal longevity) Profiles in Prognosis for HCM Sudden Death Progressive Heart Failure (obstructive) Advanced Heart Failure & End Stage (nonobstructive) AF & Stroke ICD Drugs Septal Myectomy (Alcohol Ablation) Transplant Drugs Anticoagulants Ablation

43 New HCM Paradigms: 1. Contemporary Treatable Disease Compatible w/ Low Mortality & Extended/Normal Longevity 2. Rx Interventions Are Available That Change Clinical Course of the Disease

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46 % HCM Patients Survival to Advanced Age in HC % 15 14% % 2% 70 years 75 years 80 years 90 years Survival Age

47 The ESC-HCM prediction formula for SD is as follows: Probability SCD at 5 years = exp (Prognostic index) ; where Prognostic index = [ x maximal LV wall thickness (mm)] [ x LV maximal wall thickness 2 (mm 2 )] + [ x left atrial diameter (mm)] + [ x maximal (rest/valsalva) LV outflow tract gradient (mm Hg)] + [ x family history SCD] + [ x NSVT] + [ x unexplained syncope] [ x age at clinical evaluation (years)].

48 HCM is Unpredictable

49 No. Patients 16 ICD in HCM: Time to First Shock >90 Duration (months) Maron BJ et. al. JAMA 2007;298:

50 161 saved

51 At this time we are aware of no method of management that can specifically and favorably influence the course of a patient with idiopathic ventricular hypertrophy. Eugene Braunwald Edwin C. Brockenbrough Andrew G. Morrow Circulation, Volume XXVI, August 1962

52 LGE as the Only Risk Factor A B VS LV C

53 Assessment of ESC Sudden Death Risk Score (n = 1649) % Patients With/Without ICD Intervention/Sudden Death 60% 63% 26% 9% <4% 4-6% >6% <4% 4-6% >6% Risk/5y Risk/5y Appropriate ICD Intervention ESC Risk Score No Appropriate ICD Intervention <4% 4-6% >6% Risk/5y Sudden Death

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55 % of Patients 60 56% % % 1% No. of End-Point Pathways

56 Adverse Pathway Pathway End-Point 476 Outcome 21 Death HCM 52 Death non-hcm 403 Survived AF Death HCM Death non-hcm Survived Death HCM Death non-hcm Survived

57 2 Adverse Pathways 8 Death - HCM Death - non-hcm 109 Survived 10 Death - HCM 204 (9%) HF + SD 38 4 Death - non-hcm 24 Survived 2 Death - HCM 12 1 Death - non-hcm 9 Survived

58 2 y HCM Diagnosis (SD in 2 brothers) #1 #2 #3 #4 #5/6 ICD interventions #7 #8 # Asymptomatic ICD implant Heart failure Myectomy

59 3 Adverse Pathways HCM-related 6 27 (1%) 7 Died 1 Non- HCM-related 20 Survived NYHA I/II = 16 III = 4

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62 Proportion of Patients Surviving Time (years) %/year 1.2 %/year 2.4 %/year p= Pathway = 0 Pathway = 1 Pathway = 2 Pathway =

63 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

64 ICD in HCM for Children / Adolescents 224 No. Patients 43 Appropriate ICD Discharge (19%) Follow-up= 4.3 ± 3.3 yr 4.4% / yr Initial shock 9-23 y (mean= 17 y) 13%/yr 3%/yr 2 prevention 1 prevention Maron BJ et. al. JACC 2013; 61:

65 No. Patients 16 ICD in HCM - II: Time to First Shock >90 Duration (months) Maron BJ et. al. JAMA 2007;298:

66 HCM is Unpredictable

67 Profiles in Prognosis for HCM Sudden Death Risk Symptom Progression End- Stage AF

68 CARDIA N=4,111;23-35 y 0.17% Rural Minnesota N=15,137;16-87 y 0.19% Japan N=3,354;20-77 y 0.17% Amer Indians N=3,501;51-77 y 0.2% General Population 1: ,000 people in U.S. China N=8,080;18-74 y 0.16% Tanzania N=6,680;22-91 y 0.2% AT RISK: 50, ,000?

69 A B C VS LV VS RV Prevalence of LGE = 55-70% D E F LA LA

70 Genetic Testing Prognosis To identify HCM (w/ LVH) HCM (w/o LVH) Genotype + Phenotype - Follow-up

71 Evidence for Decreased HCM Mortality: 2000 Patients Presenting in Mid-Life (30-59y) MHIF/Tufts What is Possible..

72 Unexplained LVH Sarcomeric Protein Mutations Non-Sarcomeric Mutations ~ 11 Genes--- or more? > 1500 mutations AMP-Kinase (PRKAG2) Lamp2 (Danon) Storage Diseases Fabry Disease

73 HCM Is A Global Disease 50 countries.all continents

74 N Engl J Med 1980;303:322.

75 Dr. Michele Mirowski

76 Sudden Death in Young Athletes HCM (36%) Dilated CM (2%) Coronary Anomalies (17%) Maron, BJ et. al. Circulation :

77 K.K. 23 Years with ICD and HCM 5 y 9 y 8 y BD: 2/19/ Brother SD (HCM) ICD implant Shock Polymorphic VT (203/min) VF x2 shocks (2 mo. apart) AF* (cardioverted) Amio 200 mg Xeralto * preceded by asymptomatic AF on ICD (3 weeks)

78 25-Year Contemporary Initiatives in Hypertrophic Cardiomyopathy Genetic (molecular) Single sarcomere mutation hypothesis Clinicians Lives Saved Improved Quality of Life 0 Thousands 0 Many thousands

79 Septal Scarring Post-ablation Post-myectomy Septal Scar VS=30% LV 10% No Scar Valeti et. al. JACC 2007;49:350

80 LGE as the Only Risk Factor A B VS LV C Maron BJ et. al. AJC 2008; 101(4):544-7

81 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

82 Cumulative survival in NYHA Class I-II (%) Impact of Outflow Obstruction (> 30mmHg) on Progression to Severe Heart Failure - Related Symptoms and Death in 1101 HCM Patients Nonobstructive p= RR= 4.4 Obstructive Years from First Gradient Measurement Maron,MS NEJM 2003:348:295

83 Cardiovascular Societies & HCM Consensus Panels for Myectomy vs. Alcohol Ablation ACC 2003 ESC 2003 ACC 2011 AHA 2011 Myectomy Myectomy Myectomy Myectomy

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85 HCM : The Tip Of The Iceberg Identified? Unidentified

86 No. Affected / Million The Uncommon Diseases

87 CONTEMPORARY HCM MORTALITY BY AGE: MHIF/Tufts 2015 <29 y y >60 y Total No. Patients HCM Mortality %/y 0.5%/y 0.6%/y 0.5%/y

88 Clinical Course in 70 HCM Patients with LV Apical Aneurysms 70 HCM patients with LV Apical Aneurysms 41 Alive without Events 9 Apical thrombus identified without thromboembolic history 11 Deaths HCM related death/event rate= 8.1% / year 18 Alive with HCM Events 5 HF Death 2 SCD 4 1 Thromboembolic event 6 years prior to death ICD OOHCA interventions 2 Transplant listing 2 Transplant 3 Noncardiac Thromboembolic event

89 Operative Mortality Associated with Septal Myectomy* at North American Hypertrophic Cardiomyopathy Centers, Operative Deaths** Institution No. Myectomies Age (years) % Male No. % Mayo Clinic (Rochester, MN) Cleveland Clinic 1470 Δ Tufts Medical Center (Boston) Toronto General Mount Sinai-St. Luke s (NYC) ± Totals 3, Symbols: * does not include myectomy associated with valve replacement, coronary artery bypass grafting or resection of a subaortic membrane ** within 30 days of the myectomy includes 2 patients with prior alcohol septal ablation; with these 2 patients considered non-pure myectomies, the Mayo mortality rate would be only 0.15% newest myectomy center with operations performed over only 11 years with first procedure in 2004, while data for the other centers encompasses 15 years Δ includes 19% of patients with mitral valve repair Abbreviations: MN = Minnesota; NYC = New York City

90 HCM is Unpredictable

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92 (<1%) (15%) (7%) (<1%) (7%) (<1%) (<1%) (15%) (<1%) (<1%)

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95 % HCM Mortality %/y Early HCM Referral Cohorts HCM Cohorts: Prior to utilization of current treatment strategies/ interventions 1 1.5%/y ICD intervention Heart transplant/surgical myectomy RCA/defibrillation/hypothermia %/y Present HCM Cohorts: Contemporary treatment 0.8%/y 0 HCM-Related Mortality General U.S. Population

96 2 prevention Cardiac arrest/sustained VT 1 prevention Family history HCM-SD Unexplained syncope Multiple-repetitive NSVT (Holter) Abnormal exercise BP response LGE 15% of LV mass Massive LVH 30 mm Rare subgroups/potential arbitrators End-stage (EF < 50%) LV apical aneurysm Marked LV outflow obstruction (rest) Modifiable Intense competitive sports CAD LGE 15% of LV mass Age 60y Alcohol septal ablation (?) Highest Intermediate Lowest ICD

97 Annual Mortality (%/year) %/y 1 0.8%/y 0.8%/y %/y 0.5%/y 0 86 ICD Interventions 45 Heart Transplants 30 RCA (+ hypothermia) Current Mortality General Population

98 Benign/Stable (normal longevity) Profiles in Prognosis for HCM Sudden Death Progressive Heart Failure (obstructive) Advanced Heart Failure & End Stage (nonobstructive) AF & Stroke ICD Drugs Septal Myectomy (Alcohol Ablation) Transplant Drugs Anticoagulants RF Ablation