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HCM Is A Global Disease 50 countries….all continents General Population 1:500 600,000 people in 600,000 people in U.S. U.S. AT RISK: 50,000 – 100,000 ? Amer Indians N=3,501;51-77 y 0.2% CARDIA N=4,111;23-35 y 0.17% China N=8,080;18-74 y 0.16% Rural Minnesota N=15,137;16-87 y 0.19% Japan N=3,354;20-77 y 0.17% Tanzania N=6,680;22-91 y 0.2% HCM: The Tip Of The Iceberg Identified Unidentified ?

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HCM Is A Global Disease

50 countries….all continents

GeneralPopulation

1:500

600,000 people in 600,000 people in U.S.U.S.

AT RISK:50,000 – 100,000 ?

Amer IndiansN=3,501;51-77 y

0.2%

CARDIAN=4,111;23-35 y

0.17%

ChinaN=8,080;18-74 y

0.16%

Rural MinnesotaN=15,137;16-87 y

0.19%

JapanN=3,354;20-77 y

0.17%

TanzaniaN=6,680;22-91 y

0.2%

HCM: The Tip Of The Iceberg

Identified

Unidentified?

w

Symptom Onset (43%)

Family Screening (13%)

Routine Exam (33%)

Sports/Other Screening (4%)

Acute Event (11%)

Clinical Recognition of HCM

Adabag et.al. AJC 2006;98:1507

HeterogeneityHeterogeneity

Asymmetrical hypertrophic cardiomyopathyAsymmetrical hypertrophy of the heartAsymmetrical septal hypertrophy Brock’s diseaseDiffuse muscular subaortic stenosisDiffuse subvalvular aortic stenosisDynamic hypertrophic subaortic stenosisDynamic muscular subaortic stenosisFamilial hypertrophic subaortic stenosisFamilial hypertrophic cardiomyopathyFamilial muscular subaortic stenosisFamilial myocardial diseaseFunctional aortic stenosisFunctional hypertrophic subaortic stenosisFunctional obstructive cardiomyopathyFunctional obstruction of the left ventricleFunctional obstructive subvalvular aortic stenosisFunctional subaortic stenosisHereditary cardiovascular dysplasiaHYPERTROPHIC CARDIOMYOPATHY (HCM)Hypertrophic constrictive cardiomyopathy) Hypertrophic hyperkinetic cardiomyopathyHypertrophic infundibular aortic stenosisHypertrophic nonobstructive cardiomyopathyHypertrophic obstructive cardiomyopathy (HOCM)Hypertrophic stenosing cardiomyopathyHypertrophic subaortic stenosis

Idiopathic hypertrophic subvalvular stenosisIdiopathic muscular hypertrophic subaortic stenosisIdiopathic muscular stenosis of the left ventricleIdiopathic myocardial hypertrophyIdiopathic stenosis of the flushing chamber of LVIdiopathic ventricular septal hypertrophyIrregular hypertrophic cardiomyopathyLeft ventricular muscular stenosisLow subvalvular aortic stenosisMuscular aortic stenosisMuscular hypertrophic stenosis of LVMuscular stenosis of the left ventricleMuscular subaortic stenosisMuscular subvalvular aortic stenosisNon-dilated cardiomyopathyNonobstructive hypertrophic cardiomyopathyObstructive cardiomyopathyObstructive hypertrophic aortic stenosisObstructive hypertrophic cardiomyopathyObstructive hypertrophic myocardiopathyObstructive myocardiopathyPseudoaortic stenosisStenosing hypertrophy of the left ventricleStenosis of the ejection chamber of LVSubaortic hypertrophic stenosisSubaortic idiopathic stenosisSubaortic muscular stenosis

27 yr/old femaleGenotyped based on +FH (MyBPC)/Phenotype (-)

33 yr/old nowand development of LVH and SAM;Phenotype (+)

Age 27y

Age 33y

Maron, BJ et. al.JACC 2001;38:315

ARV

LV

VS

*

*

*

RVVS

LV

BEcho CMR

Hypertrophic Cardiomyopathy

Sarcomeric ProteinMutations

Non-Sarcomeric Mutations

AMP-Kinase(PRKAG2)

Lamp2Lamp2(Danon)(Danon)

Storage Diseases

~ 11 Genes---or more?

> 1000 mutations

FabryDisease

Ao

LVFW

VS

A B

D

C

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Survival with HCM in an Unselected Cohortof Adults (Diagnosis > age 20)

Duration from Initial Diagnosis (years)

Cu

mu

lati

ve S

urv

ival

Rat

e

HCM

U.S. NationalHealth Statistics

n=234Avg. follow-up=8.1 yearsHCM mortality rate=1.2%/yrp=0.22

Maron BJ et al. JAMA 2008

HCM:A Bad Disease ?… Or

a Disease That Can BeBad ?

Profiles in Prognosis for HCM

SuddenDeathRisk

SymptomProgression

End-Stage

AF

Arrhythmogenic Myocardial Substrate in HCM

0

2

4

6

8

10

12

14

16

5-15 16-25 26-35 36-45 46-55 56-65 66-75 >75

Stroke

Heart Failure

Sudden

% H

CM

Mo

rtal

ity

Per

Ag

e G

rou

p

Age at Death or Most Recent Evaluation (years)

Maron, BJ et. al. Circulation 2000;102:858

HCM(36%)

CoronaryAnomalies

(17%)

Myo

card

itis

(6%

)

AR

VC

(4%

)

Ion

Cha

nnel

(4%

)

MVP

(4%

)

LAD Brid

ge (3%

)

CAD (3%)

Aortic Rupture (3%)AS (3%)

Other †(5%)

Dilated CM (2%)

WPW (2%)

Possible HCM* ( 8%

)

Sudden Death in Young Athletes

Maron, BJ et. al. Circulation 2009;119:1085-1092

Bethesda Conference # 36Recommendations

Athletes with the unequivocal diagnosis of hypertrophic cardiomyopathy should notparticipate 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 outflowobstruction.

HCM: identification of high risk patients

?

0.80

0.85

0.90

0.95

1.00

0 0.5 1 1.5 2 2.5 3Follow-up Duration (years)

p = 0.5

Eve

nt-

free

rat

e

DE (+)DE (-)

N = 202

N=202

Follow-up: 681 + 249 days

DE vs. Events

Highest

Intermediate

Lowest

ICD

2° preventionCardiac arrest/sustained VT

1° preventionFamilial sudden deathUnexplained syncopeMultiple-repetitive NSVT (Holter)Abnormal exercise BP response

Massive LVH

Potential arbitratorsEnd-stage phaseLV apical aneurysmMarked LV outflow obstruction (rest)Extensive delayed enhancementModifiable

Intense competitive sportsCAD

Alcohol septal ablation (?)Mutations ±

0

246

8101214

16

<15 16-19 20-24 25-29 30

Max. LV Wall Thickness (mm)

% P

atie

nts

Wit

h S

CD

Relation Between LV Thickness & SCD in 482 HCM Patients

A C

D E F

LA

P

D D

PVS

VS

B

P

D

** *

**

*

Figure 1.

Patients withLVAA(n=28)

AbortedCardiacArrest

(2)✝

ProgressiveHeart Failure/

Death(5)✝

SuddenDeath

(2)*

non-fatalembolicstroke

(1)

non-fatalembolicstroke

(1)

AppropriateICD Discharge

(3)*

Alive/Clinically

Stable(n = 16)*

AdverseEvents(n = 12)

Cardiovascular Event Rate = 11%/year

Foci For Ventricular Arrhythmias?

RV

LVVS

0102030405060708090

100

NSVT Couplet PVC SVT

Any DE

No DE

p<0.001

p=0.001

p=0.01

p=0.06

% o

f H

CM

Pat

ien

ts w

ith

Arr

hyt

hm

ia

24-hour Holter Arrhythmia and DE

VS

LVAML

FW

A B

C

DE as the Only Risk Factor

Prevention of Sudden DeathPrevention of Sudden Death

In HCMIn HCM

Amio

0

5

10

15

20

25

30

% O

n D

rug

w/ S

ud

den

Dea

th

VerapamilBeta-

Blocker Disopyramide

27%

15%17%

20%

Drugs Do Not Protect AbsolutelyFrom Sudden Death In HCM

N Engl J Med 1980;303:322.

35 y – Brother SD

36 y – ICD

40 y – Generator replaced

41 y –Appropriate

shock #1

50 y –Appropriate shock #2

52y – Present

5 y:

9 y:

HCM is Unpredictable

0

2

4

6

8

10

12

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

No.

of E

vent

s

NoonMid-night

Circadian Variability for Appropriate ICD Shocks

Maron, BJ et. al.Heart Rhythm 2009;6:599

<10

11-15

16-20

21-25

26-30

31-35

36-40

41-45

46-50

51-55

56-60

61-65

66-70

71-75

>76

No

. of P

atie

nts

Age At Implant (years)

ICD in HCM : Age at ImplantICD in HCM : Age at Implant

0

10

20

30

40

50

60

70

Maron, BJ et. al.JAMA 2007;298:40

506

103

11%

ICD in HCM: 2007ICD in HCM: 2007

5.5%/ yr

Follow-up = 3.7 ± 3 years

ICD dischargerate

Appropriate ShocksVT/VF (20%)

4%

2º prevention 1º prevention Maron, BJ et. al.JAMA 2007;298:40

High-Risk Children with HCM and ICDs

Implanted < 20 years:Appropriate shocks:Age at intervention:

Implanted < 15 years:Appropriate shocks:Age at intervention:

8323 (28%;7%/y%/y)18 + 4 years

3713 (35%;11%/y11%/y)15 + 3.6 years

0

1

2

3

4

5

6

7

1 2 ≥ 3No. Risk Factors for Primary Prevention

Rat

e of

App

ropr

iate

Sho

cks

(100

per

son-

yr)

3.7

3.0

4.6

Overall p=0.88

33% of appropriate

shocks

Maron, BJ et. al. JAMA 2007;298:40

2.0

2.8 2.9

5.0

0

1

2

3

4

5

6

MassiveLVH

Family SD NSVT(Holter)

Syncope

Ap

pro

pri

ate

Sh

ock

Rate

s/Y

ear

One Risk Factor Patients With Primary Prevention

Maron, BJ et. al. JAMA 2007;298:4

≤ 34 - 6

7 - 1011-20

21-3031-40 51-60

>90

Duration (months)

No

. Pat

ien

ts

0

2

4

6

8

10

12

14

16

61-7071-90

41-50

ICD in HCM - II: Time to First Shock

HCM—ICD Registry

29(6%)

14

14

1

Deaths

ICDMalfunction

End-stageEmbolic stroke

Cancer, sepsis,renal diseases,suicide, CAD,

accidents

No HCM

HCM

HCM-Arrhythmias

(nl EF)

Maron, BJ et. al. JAMA 2007;298:4

After the Shock?

Moss et. al. MADIT-IICirculation 2004110:3760-65

Trading SD for CHF

1

4

NYHA Class:Initial VT/VF

25

5

2 3

4

25

23

2

1

I

II

III

1

NYHA Class:At follow-up

Clinical Status Post—Appropriate ICD Shock

90%

Maron, BJ et. al. Heart Rhythm 2009; 6:993

High--risk

Somerisk

Cardiologist

Patient Autonomy

TRANSPARENCY / FULL DISCLOSURE / INFORMED CONSENT

?

Risk FactorsRisk Factors

Primary Prevention Decision Tree: ICD In HCMPrimary Prevention Decision Tree: ICD In HCM

United States

Germany

Canada

Ireland

Denmark

Belgium

Italy

Netherlands

Australia

Austria

Switzerland

Norway

Sweden

Finland

France

New Zealand

United Kingdom

Japan

Spain

Portugal

Defibrillator Implants Throughout The World (per million population)

421133

104

10291

87

8684

8277

66

54

46

4544

41

4033

27

17

Profiles in Prognosis for HCM

SuddenDeathRisk

SymptomProgression

End-Stage

AF

Beta-blocker

Verapamil

Beta-blocker

Verapamil

Verapamil+ Diuretic

Beta-blocker+ Diuretic

SubaorticObstruction

DDD Pacing

Septal Septal MyotomyMyotomy--MyectomyMyectomy

Nonobstructive

HeartTransplantation

Disopyramide

Diltiazem

Beta-blocker+ Verapamil

Management of HCMAsymptomatic

Mild-ModerateSymptoms

Severe Symptoms

? ?

Treatment Failure

RefractorySevere

Symptoms

AlcoholSeptal

Ablation

1086420

100

80

60

40

20

0

Nonobstructive

Obstructive

Years from First Gradient Measurement

Cu

mu

lati

ve s

urv

ival

in N

YH

A C

lass

I-I

I (%

)

p=0.0001RR= 4.4

Impact of Outflow Obstruction (> 30mmHg) on Progression to Severe Heart Failure - Related

Symptoms and Death in 1101 HCM Patients

Maron,MS NEJM 2003:348:295

0

50

100

150

200

250

Rest Post-Exercise

LV

Ou

tflo

w G

rad

ien

t (m

mH

g)

Ө

Ө

Maron MS, Circulation, in press, in press MS, CirculatioMaron MS, Circulation, in pressMaron, MS, Circulation, in press

Case for Septal Myectomy: The Gold Standard

• 45 years of experience

• Low operative mortality ( ≤ 1%) & virtually zero last 10 y @

major centers) --- lower than ablation

• Permanent, virtually complete reduction LVOTG to 0-10mmHg

• 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 MyectomySurgical Septal Myectomy

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10

Years Post-op

Su

rviv

al

Isolated MyectomyNonoperated obstructiveExpected ---US population

P<0.001 83%

61%

Ommen, S et. al. JACC 2006

Septal Ablation: HCM

Major Issues with Alcohol Septal Ablation

• Short follow-up: Is gradient / symptom relief long-lasting?

• Residuals common –ie. PMK and ICD (20%)

• 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

Septal ScarSeptal Scar No Scar No Scar

PostPost--ablationablation PostPost--myectomymyectomy

VS=30%VS=30%LV10%LV10%

Valeti et. al. JACC 2007;49:350

0

5

10

15

20

25

30

Sorajja Cuoco Noseberry Maron van derLee

Ventricular Tachyarrhythmias and Sudden DeathFollowing Alcohol Septal Ablation

% P

atie

nts

With

Sus

tain

ed V

T/V

F/S

D

5%7%

24% 25%

10%

SuddenDeath

Progressive Heart Failure

AF&

Stroke

End-Stage

Profiles in Prognosis for HCM

Benign/Stable(normal longevity)

Clinical Pathways of Prognosis in HCM

ICD

SDProgressive

HFEnd

Stage

AF &

Stroke

NormalLongevity

DrugsMyectomy

(alcohol ablation)

Transplant Drugswarfarin

RFA

SuddenDeathRisk

SymptomProgression

End‐Stage

AF

ICD

Benign/Stable(normal longevity)

Profiles in Prognosis for HCM

0

500

1000

1500

2000

2500

HCM

Cystic

Fibrosis

Multiple

Sclerosis

Muscular

Dystrophy

LQTS

Marfan

ALS

Brugada

Ataxia

No. A

ffected / M

illion

The“Uncommon” Diseases

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 2005;46:480

HCM and Race

Hospital – BasedHCM Patients(n=1,986)

Competitive Athletes:HCM-relatedSudden Death (n=102)

White(45%)

White(92%)

African-American (55%)

African-American (8%)

Bethesda Conference # 36

ClassificationSports (#8)

Consensus Panels

#2 #3 #4 #5 #6 #7

#1 #9 #10 #11 #12

Congenital Valvular

Screening / Dx

HCMOther C-M

MVPMyocarditis

Drugs

HTN

AED

CAD

Commotio Legal

Arrhythmias

(Exercise)(106; 33%)

Rest Obstruction(119; 37%)

Non-Obstructive(95; 30%)

70%

Provokable Obstruction

HCM is a Predominantly ObstructiveObstructive Disease

39Cardiac Arrest

ICD Shock

7

Died

Non-HCM (2)

End-stage (4)

SCD (1)

Survived

32

15 17

No recurrence

Recurrentcardiac arrest/

ICD shock

8 + 7 y(up to 30 y)

10 + 8 yMaron, BJ et. al.Heart Rhythm 20096:993-997

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

ICD : HCM vs. CAD

CAD HCM

Implant age ~65 ~40

Risk period short long

Substrate often usually compromised intact

Intervention / yr ~30% 5%

DeathsN = 29 (6%)

• No–HCM: 14cancer / sepsisrenal suicideaccidentsCAD

• HCM: 14End-stageEmbolic stroke

• HCM – Arrhythmia: 1

(ICD malfunction)

0123456789

10

Deaths AbortedSD

FailedProcedure

App. ICDShocks

PMK MI

Short and Long-Term Outcome After Alcohol Septal Ablationfor Obstructive HCM (91 patients)

“…about one-third of HCM patients who underwent alcohol septal ablation…developed one or more cardiovascular

complications over…5.6 years”tenCate et. al.ThoraxcentrumRotterdam, The Netherlands

n=9

n=7 n=7

n=4 n=4

n=2

1086420

100

80

60

40

20

0

Nonobstructive

Obstructive

Cu

mu

lati

ve S

urv

ival

(%

)

p<0.02

Years from First Gradient Measurement

Impact of Outflow Obstruction (> 30mmHg) on Risk For Sudden Death in 1101 HCM Patients

Other Possible Contributing Risk Factors

• LV outflow obstruction

• Myocardial ischemia

• Bridged LAD

• AF

•• Alcohol Septal AblationAlcohol Septal Ablation

In Individual HCM Patients

Clinical Implications of LAMP2 Cardiomyopathy

• Survival after age 25 years unlikely

• Requires molecular diagnosis

• Deserves consideration for heart transplantation

Highest

Intermediate

Lowest

ICD

Strongest Risk Factors:Cardiac arrest

Familial SDSyncopeMultiple-repetitive NSVTBP — exerciseMassive LVH

End-Stage Apical aneurysm

Malignant genotype (?)Alcohol Ablation (?)

Septal Myectomy vs. Alcohol Septal Septal Myectomy vs. Alcohol Septal Ablation:Ablation:

Appropriate ICD ShocksAppropriate ICD Shocks

No. Pts

No. Appropriate

Shocks % %/Year

Surgical myectomy

50 6 12 2.6

Alcohol septal ablation

17 4 24 10.3

4x

pp<0.01

2.0

2.8 2.9

5.0

0

1

2

3

4

5

6

MassiveLVH

Family SD NSVT(Holter)

Syncope

Ap

pro

pri

ate

Sh

ock

Rate

s/Y

ear

One Risk FactorOne Risk Factor Patients With Primary Prevention

Electronics

Battery

Hermetic Housing

Connector

- DF Feedthrough wirePolyimide tubing

+ Backfill tube Short circuit

Joshua’s Implantable DefibrillatorPrizm 2 DR Model 1861 (10/4/01)

*Guidant aware 2002

*Manufacturing changes

1- April 2002

2- November 2002*Did not inform

physicians or patients*Continued to sell units

without the changes

during 2002

BeforeIntervention

ImmediatelyAfter

Follow-up 0

20

40

60

80

100

120

Qin JX, et al. JACC 2001;38:1994-2000.

Re

stin

g L

VO

TL

VO

TG

rad

ien

tG

rad

ien

t, m

mH

g

NS

P < 0.001

P < 0.001

Ablation

Myectomy

B.B. C.C.

D.D. E.E. F.F.

A.A.

RV

VSLV

VS

HCM:A Bad Disease ?… Or

a Disease That Can BeBad ?

35 y – Brother SD

(age 39)

36 y – ICD

40 y – Generator replaced

41 y –Appropriate

shock #1

50 y –Appropriate shock #2

5 y:

9 y:

HCM Is A Global Disease

Previously Proposed Pharmacologic TherapyFor Sudden Death Prevention in HCM

•ß-adrenergic blockers•verapamil

•procainamide•quinidine

•amiodarone

proarrhythmia (obsolete)

no data

efficacy?chronic use (>3y) ?

HCM Cohorts Annual Mortality

Tertiary–referral basedChildren 4 – 6 %Children & adults 3 – 4 %

Community–based 0.5 – 1.5 %non–tertiary regionalunselected

Non-dilated

Dilated

EndEnd--StageStage

EF < 50%

LV Cavity LV Wall

0

2

4

6

8

10

12

14

16

Death Acute MI VF PMR ICD Re-Intervention

Surgery

Ablation

% o

f P

atie

nts

0

5%

0 0

2%

14%

0

9%

0

5%

3%

9%

Serruys et al.Circulation 2005; 112: 482Rotterdam Thorax Ctr.

Myectomy Ablation

0

5

10

15

20

25

Pre Post Pre Post

16

23

1619

P < 0.05

Pe

ak O

2co

nsu

mp

tio

n

(ml/

kg/m

in)

Firoozi et al. Eur Heart J 2002;23:1617.

Amer IndiansN=3,501;51-77 y

0.2%

CARDIAN=4,111; 23-35 y

0.17%

ChinaN=8,080; 18-74 y

0.16%

Rural MinnesotaN=15,137; 16-87 y

0.19%

JapanN=3,354;20-77 y

0.17%

GeneralPopulation

1:500

500,000 people in U.S.

AT RISK:50,000 – 100,000 ?

0

500

1000

1500

2000

2500

HCM

Cystic

Fibro

sis

Mul

tiple

Scler

osis

Mus

cula

r

Dystro

phy

LQTS

Mar

fan

ALSB

ruga

da

Ata

xia

No

. A

ffe

cted

/ M

illio

n

The“Uncommon” Diseases

HCM (36%)

Indeterminate LVH -possible HCM (8%)

Coronary artery anomalies (17%)

Myo

carditi

s (6%

)

ARVC (4%)MVP (4%)

Tunneled LAD (3%)

CAD (3%)

AS (3%)

Dilated C-M (2%)

Sarcoidosis (1%)Aortic rupture (2%)Ion channelopathies

Other congenital HD Other (3%) Normal heart (3%)

Sudden Death in Young Athletes

HCM Population

Heart failuresymptoms

Drugs*

Refractorycongestivesymptoms

Genetically affected

w /o phenotype

Longitudinalfollow-up †

No / mild symptoms

(low SDrisk)

No Rx Drugs*

High risk SD ICD

AFRate-control;Cardioversion;Anti-coagulation

Non-obstructive(rest & provocation)

Obstructive(rest & / or

provocation)

Surgery:Surgery:myectomymyectomy

Surgical alternatives

DDD pacing Alcohol septalablation

Heart transplantfor “end-stage”

Bethesda Conference # 26Recommendations

Athletes with the unequivocal diagnosis of hypertrophic cardiomyopathy should notparticipate 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 outflowobstruction.

Asymmetrical hypertrophic cardiomyopathyAsymmetrical hypertrophy of the heartAsymmetrical septal hypertrophy Brock’s diseaseDiffuse muscular subaortic stenosisDiffuse subvalvular aortic stenosisDynamic hypertrophic subaortic stenosisDynamic muscular subaortic stenosisFamilial hypertrophic subaortic stenosisFamilial hypertrophic cardiomyopathyFamilial muscular subaortic stenosisFamilial myocardial diseaseFunctional aortic stenosisFunctional hypertrophic subaortic stenosisFunctional obstructive cardiomyopathyFunctional obstruction of the left ventricleFunctional obstructive subvalvular aortic stenosisFunctional subaortic stenosisHereditary cardiovascular dysplasiaHYPERTROPHIC CARDIOMYOPATHY (HCM)Hypertrophic constrictive cardiomyopathyHypertrophic hyperkinetic cardiomyopathyHypertrophic infundibular aortic stenosisHypertrophic nonobstructive cardiomyopathyHypertrophic obstructive cardiomyopathy (HOCM)Hypertrophic stenosing cardiomyopathyHypertrophic subaortic stenosisIdiopathic hypertrophic cardiomyopathyIdiopathic hypertrophic obstructive cardiomyopathyIdiopathic hypertrophic subaortic stenosis (IHSS)

Idiopathic hypertrophic subvalvular stenosisIdiopathic muscular hypertrophic subaortic stenosisIdiopathic muscular stenosis of the left ventricleIdiopathic myocardial hypertrophyIdiopathic stenosis of the flushing chamber of LVIdiopathic ventricular septal hypertrophyIrregular hypertrophic cardiomyopathyLeft ventricular muscular stenosisLow subvalvular aortic stenosisMuscular aortic stenosisMuscular hypertrophic stenosis of LVMuscular stenosis of the left ventricleMuscular subaortic stenosisMuscular subvalvular aortic stenosisNon-dilated cardiomyopathyNonobstructive hypertrophic cardiomyopathyObstructive cardiomyopathyObstructive hypertrophic aortic stenosisObstructive hypertrophic cardiomyopathyObstructive hypertrophic myocardiopathyObstructive myocardiopathyPseudoaortic stenosisStenosing hypertrophy of the left ventricleStenosis of the ejection chamber of LVSubaortic hypertrophic stenosisSubaortic idiopathic stenosisSubaortic muscular stenosisSubvalvular aortic stenosis of the muscular typeTeare’s disease

0

5

10

15

20

25

30

≤50 51-59 ≥60

% M

yoca

rdiu

m w

ith

DE

Ejection Fraction (%)

p<0.001

Bypass Angioplasty Bypass Angioplasty Revascularization Investigation Revascularization Investigation

(BARI)(BARI)

Theoretical Surgical Myectomy vs. Theoretical Surgical Myectomy vs. Alcohol Septal Ablation TrialAlcohol Septal Ablation Trial

25,200Patients UndergoingCoronary Angiogram

Clinically Eligible

Enrolled and Randomized

914 915

CABG PTCA

HCM Patients to be Screened

Clinically Eligible:Obstruction & SevereRefractory Symptoms

Refuse Randomization

1,200 (3.5%) Enrolled and Randomized

600 600

Myectomy ASA

2,400 Eligible for BothMyectomy and ASA

Exclusion Criteria67%

3,400 (10%)

~ 50%

4,110

12,530 (50%)

RefusedRandomization55%

Eligible for Both CABG and PTCA

Exclusion Criteria~30%

1,829 (7%)

34,000

Profiles in Prognosis for HCM

SuddenDeathRisk

SymptomProgression

End-Stage

AF

ICD

Sudden Heart Failure Stroke0

10

20

30

40

50

60

70

80

Mode of HCM Death

Ag

e a

t D

eath

(ye

ars

)

Hypertrophic Cardiomyopathy

Sarcomeric ProteinMutations

Non-Sarcomeric Mutations

AMP-Kinase(PRKAG2)

Lamp2(Danon)

Storage Diseases

~ 11 Genes---or more?

> 400 mutations

FabryDisease

Case for Septal Myectomy: The Gold Standard

• 45 years of experience

• Permanent, virtually complete reduction LVOTG to

0-10mmHg

• 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 optionParticularly, for younger patients w/

substantial life expectancy

Ablation

Alternative optionParticularly, poor operative candidates

significant co-morbidityadvanced agereject surgery

0

10

20

30

40

50

60

70

NYHA III/IV Post-OpRest

Gradient

Post-OpProvocable

Gradient

Late CVDeath

Failure

% o

f P

atie

nts

AblationMyectomy

59%

0%

12%

0%

6%

14%

42%

5%

15%

28%

p < 0.001

p < 0.001

p < 0.001

p < 0.001

p < 0.001

Ralph-Edwards et al.J Thorac CV Surg 2005; 129: 351

45 years 5 yr

~ 3,000 > 3,500

Surgery Ablation

Time

Cases

Ablation > Surgery by 10-35x in last 5 years

A B

C D

Ao

LVFW

VS

Case for Septal Myectomy: The Gold Standard

• 45 years of experience

• Permanent, virtually complete reduction LVOTG to

0-10mmHg

• 90%: 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 y @ 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.

1086420

100

80

60

40

20

0

Nonobstructive

Obstructive

Cu

mu

lati

ve S

urv

ival

(%

)

p<0.02

Years from First Gradient Measurement

Impact of Outflow Obstruction (> 30mmHg) on Risk For Sudden Death in 1101 HCM Patients

0

100

200

300

400

500

600

700

800

900

Mayo Clinic ClevelandClinic

TorontoGeneral

Co

nse

cuti

ve P

ure

Mye

cto

my

Pat

ien

tsw

/o A

n O

per

ativ

e D

eath

1600

Total

1538

No Mutation

62%

MYBPC316%

MYH714%

MYL2 – 2%

TNNT2– 1.5%

TNNI3– 1%

TMP – 0.5%ACTC – 0.3%

Multiple mutations– 3%

Distribution of Disease - Causing Mutations in HCM Cohort

from Van Driest and Ackerman (Mayo); 2004

90

91

92

93

94

95

96

97

98

99

100

1 2 3 4 5 6 7 8 91011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859606162636465

Per

cen

t L

ead

Su

rviv

al

Sprint Quattro Secure model 6947

Sprint Fidelis model 6949

P=0.005

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65

Implant Months

Obstacles From Industry

Major Issues with Alcohol Septal Ablation

• Short follow-up: Is gradient / symptom relief long-lasting?

• Residuals common –ie. PMK and ICD (20%)

• Relatively high rate of repeat procedures (25%)

• Often not successful w/ high gradients

• Myectomy after failed ablations is difficult

• Anatomic inflexibility – perforator distribution

HCM DISEASE SPECTRUM

Marked OutflowObstruction

+Severe Symptoms

(5%)

0

5

10

15

20

25

<10 11-1516-2021-2526-3031-3536-4041-4546-5051-5556-6061-6566-7071-75 >76

No

. of

Pat

ien

ts

Age At Implant (years)

ICD in HCM: Age at Implant

Major Issues: Alcohol Septal Ablation

• Short follow-up: Is gradient / symptom relief long-lasting?

• Residuals common –ie. PMK and ICD (20%)

• 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

HCM Population

Heart failuresymptoms

Drugs*

Refractorycongestivesymptoms

Genetically affected

w /o phenotype

Longitudinalfollow-up †

No / mild symptoms

(low SDrisk)

No Rx Drugs*

High risk SD ICD

AFRate-control;Cardioversion;Anti-coagulation

Non-obstructive(rest & provocation)

Obstructive(rest & / or

provocation)

Surgery:Myotomy-myectomy

Surgical alternatives

DDD pacing Alcohol septalablation

Heart transplantfor “end-stage”

%

Pat

ien

ts in

Ag

e G

rou

ps

Wit

h M

ax.

LV

>3

0m

m

Age at Initial Evaluation

0

5

10

15

20

25

0-10 11-20 21-30 31-40 41-50 51-60 61-70 >70

Max. LV = 30-34mm

Max. LV 35mm

Relationship of Massive LVH to Age in HCM

Primary Prevention of SD in HC1 or 2 risk factors required?

---Individualization---

“Over-treatment” vs. “under-treatment”

Imperfect riskstratification

Perceivedliability

ICD is more powerful than our present ability to precisely identify all high risk patients

45 years 5 yr

~ 3,000 > 3,500

Surgery Ablation

Time

Cases

Ablation > Surgery by 10-35x in last 5 years

5

0.4

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 6 7 8 9 10

Years Post-op

Ove

rall

Su

rviv

al

Myectomy

Nonoperated obstructiveExpected ---U.S. population

0.5

Myectomy Enhances Long-term Survival

83%83%

61%61%

p=0.001p=0.001

0

50

100

150

200

250

Rest Post-Exercise

LV

Ou

tflo

w G

rad

ien

t (m

mH

g)

Ө

Ө

Maron MS, Circulation, in press, in press MS, CirculatioMaron MS, Circulation, in pressMaron, MS, Circulation, in pressMaron MS, Circulation, in press

Family Screening Strategies to Detect HC With Echo / ECG (Absent Genetic Testing)

•< 12 years oldoptional unless:

malignant familycompetitive athletesuspicion of early onset LVH

•12 to 18 years oldq 12 - 18 mo.

•> 18 years oldq 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

• Ventricular pre-excitation

(often)

• Young males < 25 y• Massive LVH (35 ± 15 mm)

• Tall ECG voltages

• Abnormal chemistries

ALT / CPK

Cardiac Danon(Lamp 2)

HCM Cohorts Annual Mortality

Tertiary–referral basedChildren 4 – 6 %Children & adults 3 – 4 %

Community–based 0.5 – 1.5 %non–tertiary regionalunselected

Barry J. Maron, MD

No. HCM Patients 958

• Referrals for surgical myectomy 114 (12%)

• Referred for alcohol ablation 14 (1%)

• Total Interventions (~ 9 pts / yr) 128 (13%)

Interventions for Obstructive HCMMinneapolis 1993 – 2006 (14years)

(Exercise)(106; 33%)

Rest Obstruction(119; 37%)

Non-Obstructive(95; 30%)

70%

Provokable Obstruction

Maron MS, Circulation,in press

0

20

40

60

80

100

120

5 10 15 20 25

Years From HCM Diagnosis

Per

cen

t S

urv

iva

l

HCM

Gen. Pop.HCM

P=0.20

P=0.001

Survival With HCM According to Age at Diagnosis

≥ 50 yrGen. Pop.

< 50 yr

Risk Stratification and ICD Risk Stratification and ICD DecisionDecision--Making in HCMMaking 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

No. HC Patients 725

• Referrals for surgical myectomy 20 (2.8%)

• Referred for alcohol ablation 5 (0.7%)

• Total Interventions (~ 2 pts / yr) 25 (3.5%)

Interventions for Obstructive HCMinneapolis 1993 – 2003 (10 years)

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

ICD : HCM vs. CADCAD HCM

Implant age ~65 ~40

Risk period short long

Substrate often usuallycompromised intact

Intervention / yr ~30% 7%

The Oukrop Family

ICD ICD: 10/4/01

0

500

1000

1500

2000

2500

HCM

Cystic

Fibro

sis

Mul

tiple

Scler

osis

Mus

cula

r

Dystro

phy

LQTS

Mar

fan

ALSB

ruga

da

Ata

xia

No

. A

ffe

cted

/ M

illio

n

The“Uncommon” Diseases

Asymmetrical hypertrophic cardiomyopathyAsymmetrical hypertrophy of the heartAsymmetrical septal hypertrophy (ASH)Brock’s diseaseDiffuse muscular subaortic stenosisDiffuse subvalvular aortic stenosisDynamic hypertrophic subaortic stenosisDynamic muscular subaortic stenosisFamilial hypertrophic subaortic stenosisFamilial hypertrophic cardiomyopathy (FHC)Familial muscular subaortic stenosisFamilial myocardial diseaseFunctional aortic stenosisFunctional hypertrophic subaortic stenosisFunctional obstructive cardiomyopathyFunctional obstruction of the left ventricleFunctional obstructive subvalvular aortic stenosisFunctional subaortic stenosisHereditary cardiovascular dysplasiaHYPERTROPHIC CARDIOMYOPATHY (HCM)Hypertrophic constrictive cardiomyopathyHypertrophic hyperkinetic cardiomyopathyHypertrophic infundibular aortic stenosisHypertrophic nonobstructive cardiomyopathyHypertrophic obstructive cardiomyopathy (HOCM)Hypertrophic stenosing cardiomyopathyHypertrophic subaortic stenosisIdiopathic hypertrophic cardiomyopathyIdiopathic hypertrophic obstructive cardiomyopathyIdiopathic hypertrophic subaortic stenosis (IHSS)

Idiopathic hypertrophic subvalvular stenosisIdiopathic muscular hypertrophic subaortic stenosIdiopathic muscular stenosis of the left ventricleIdiopathic myocardial hypertrophyIdiopathic stenosis of the flushing chamber of LVIdiopathic ventricular septal hypertrophyIrregular hypertrophic cardiomyopathyLeft ventricular muscular stenosisLow subvalvular aortic stenosisMuscular aortic stenosisMuscular hypertrophic stenosis of LVMuscular stenosis of the left ventricleMuscular subaortic stenosis (MSS)Muscular subvalvular aortic stenosisNon-dilated cardiomyopathyNonobstructive hypertrophic cardiomyopathyObstructive cardiomyopathyObstructive hypertrophic aortic stenosisObstructive hypertrophic cardiomyopathyObstructive hypertrophic myocardiopathyObstructive myocardiopathyPseudoaortic stenosisStenosing hypertrophy of the left ventricleStenosis of the ejection chamber of LVSubaortic hypertrophic stenosisSubaortic idiopathic stenosisSubaortic muscular stenosisSubvalvular aortic stenosis of the muscular typeTeare’s disease

0

50

100

150

200

250

Rest Post-Exercise

LV

Ou

tflo

w G

rad

ien

t (m

mH

g)

Ө

Ө

Maron MS, Circulation, in press, in press MS, CirculatioMaron MS, Circulation, in pressMaron, MS, Circulation, in pressMaron MS, Circulation, in press

(Exercise)(106; 33%)

Rest Obstruction(119; 37%)

Non-Obstructive(95; 30%)

70%

Provokable Obstruction

Maron MS, Circulation,in press

Other Possible Contributing Risk Factors

•• LV outflow obstructionLV outflow obstruction

• Myocardial ischemia

• Bridged LAD

• AF

• Alcohol Septal Ablation

In Individual HCM Patients

LVLV

RVRV

LVLV

RVRV

vs vs

NYHA III; EF 40%; 30% DE NYHA I; EF 65%; 46% DE

Subsequent Events

• June: Guidant recalled 26,000 Prizm 2 DR ICDs.

• June: Guidant recalled 16,000 Contak ICDs after a patient died due to a short-circuit problem the company had identified a year earlier.

• June: Guidant recalled 21,000 AVT ICDs.

• June: Guidant recalled 46,000 Renewal ICDs.

• July: Guidant recalled 28,000 pacemakers that were prone to abrupt failure and runaway pacing that caused at least one death.

> 180,000 devices

Late Onset LVH

0

5

10

15

20

25

30

≤50 51-59 ≥60

% M

yoca

rdiu

m w

ith

DE

Ejection Fraction (%)

p<0.001

HCM and Race

Hospital – BasedHCM Patients

(n=1,986)

Competitive Athletes:HCM-related

Sudden Death (n=102)

White(45%)

White(92%)

African-American (55%)

African-American (5%)

Commercial Diagnostic Genetic Testing for HCM

• Laboratory of Molecular Medicine (Partner’s Health Care; Harvard Medical School)

• http://www.hpcgg.org/lmm

• Tests for known and novel mutations in 10 most common HCM genes

• 7 cc blood

• Results: ≤ 4 weeks

• Cost: $2800; $200 / each relative

• Limitations:- cost- false negatives

High-Risk Children with HCM and ICDs

Implanted < 20 years:Appropriate shocks:Age at intervention:

Implanted < 15 years:Appropriate shocks:Age at intervention:

8323 (28%;7%/y%/y)18 + 4 years

3713 (35%;11%/y11%/y)15 + 3.6 years

Case for Septal Myectomy: The Gold Standard

• 45 years of experience

• Low operative mortality ( ≤ 1%) & virtually zero last 12 y @

major centers) --- lower than ablation

• Permanent, virtually complete reduction LVOTG to 0-10mmHg

• 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 Septal Myectomy vs. Alcohol Septal Ablation:Ablation:

Appropriate ICD ShocksAppropriate ICD Shocks

No. Pts

No. Appropriate

Shocks % %/Year

Surgical myectomy

50 6 12 2.6

Alcohol septal ablation

17 4 24 10.3

4x

pp<0.01

Other Possible Contributing Risk Factors

• LV outflow obstruction

• Myocardial ischemia

• Bridged LAD

• AF

•• Alcohol Septal AblationAlcohol Septal Ablation

In Individual HCM Patients

Septal Scarring

Septal ScarSeptal Scar No Scar No Scar

PostPost--ablationablation PostPost--myectomymyectomy

VS=30%VS=30%LV10%LV10%

Septal Myectomy vs. Alcohol Septal Septal Myectomy vs. Alcohol Septal Ablation:Ablation:

Appropriate ICD ShocksAppropriate ICD Shocks

No. Pts

No. Appropriate

Shocks % %/Year

Surgical myectomy

50 6 12 2.6

Alcohol septal ablation

17 4 24 10.3

4x

pp<0.01

Bethesda Conference # 36

ClassificationSports (#8)

Consensus Panels

#2 #3 #4 #5 #6 #7

#1 #9 #10 #11 #12

Congenital Valvular

Screening / Dx

HCMOther C-M

MVPMyocarditis

Drugs

HTN

AED

CAD

Commotio Legal

Arrhythmias

CMR Delayed CMR Delayed Enhancement?Enhancement?

Symptom Onset (43%)

Family Screening (13%)

Routine Exam (33%)

Sports/Other Screening (4%)

Acute Event (11%)

Clinical Recognition of HCM

w

VS

LVAML

FW

A B

C

BA B

C D

RV

Ao

LA

VS

FW LA

LVVS

E

RVLVVS

*

Minnesota 243 (88%)Minnesota 243 (88%) Minneapolis-St. Paul83 (30%)

N. Dakota, S. Dakota,Iowa, Wisconsin

34 (12%)

N. Dakota, S. Dakota,Iowa, Wisconsin

34 (12%)

United States

Germany

Canada

Ireland

Denmark

Belgium

Italy

Netherlands

Australia

Austria

Switzerland

Norway

Sweden

Finland

France

New Zealand

United Kingdom

Japan

Spain

Portugal

Defibrillator Implants Throughout The World - 2003(per million population)

421133

104

10291

87

8684

8277

66

54

46

4544

41

4033

27

17

Amio

0

5

10

15

20

25

30

% O

n D

rug

w/ S

ud

den

Dea

th

VerapamilBeta-

Blocker Disopyramide

27%

15%17%

20%

Drugs Do Not Protect AbsolutelyFrom Sudden DeathSudden Death In HCM

1416 g

65 mm

A B

C D