profiles in prognosis for hcm - osu center for continuing ... maron - scd-icd... · profiles in...

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

600,000 people in U.S.

AT RISK:50,000 – 100,000 ?

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

StrokeHeart Failure

Sudden

% H

CM

Mor

talit

y Pe

r Age

Gro

up

Age at Death or Most Recent Evaluation (years)

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

Highest

Intermediate

Lowest

ICD

2° preventionCardiac arrest/sustained VT

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

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

Intense competitive sportsCAD

Alcohol septal ablation (?)Mutations ±

02468

10121416

<15 16-19 20-24 25-29 ≥30Max. LV Wall Thickness (mm)

% P

atie

nts

With

SC

D

Relation Between LV Thickness & SCD in 480 HCM Patients

Spirito et. al. NEJM 2000; 342:1778

Highest

Intermediate

Lowest

ICD






A C

D E F

LA

P

D D

P

VSVS

B

P

D

** *

**

*

Figure 1.Maron MS et. al. Circulation 2008; 118:1541

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

Maron MS et. al. Circulation 2008; 118:1541

Highest

Intermediate

Lowest

ICD






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/VF

/SD

5%7%

24% 25%

10%

37/386 = 10%

Highest

Intermediate

Lowest

ICD






HCM(36%)

CoronaryAnomalies

(17%)

Myo

card

itis

(6%

)

ARVC

(4%

)

Ion

Chan

nel (

4%)

MVP (4

%)

LAD Bridge (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

Hypertrophic Cardiomyopathy

Sarcomeric ProteinMutations

Non-Sarcomeric Mutations

AMP-Kinase(PRKAG2)

Lamp2Lamp2(Danon)(Danon)

Storage Diseases

~ 11 Genes---or more?

> 1000 mutations

FabryDisease

Intermediate

Low Risk

Risk Stratification for Sudden Death in HCM

Moderate

High

No risk factors

Family history of sudden death

Nonsustained VTUnexplained syncope

Extreme LVH

Abnormal BP response to Ex

Total number of sudden deaths = 22

Multicenter Study on Sudden Deathin “Low Risk” Patients with HCM

Prevalence = 3%

Incidence = 0.5%/yr

Study population = 721 “Low Risk” patients

Foci For Ventricular Arrhythmias?

RV

LVVS

0102030405060708090

100

NSVT Couplet PVC SVT

Any DE

No DE

p<0.001p=0.001

p=0.01

p=0.06

% o

f HC

M P

atie

nts w

ith A

rrhy

thm

ia

24-hour Holter Arrhythmia and Presence of DE

Adabag et. al. JACC 2008; 51:1369

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-f

ree

rate

DE (+)DE (-)

N = 202N=202

Follow-up: avg 2 years

Presence of DE vs. Events

Maron MS et. al. Circ HF 2008; 1:184

VS

LVAML

FW

A B

C

DE as the Only Risk Factor

Maron BJ et. al. AJC 2008; 101:544

Family T(as of 12-1-10)

SCD

(40s) (85)

(77)(73)

(100)(45)

MyBPC + cTnl +

(39)

MyBPC +cTnl +

(32)

cTnl +

(4)MyBPC +cTnl +

Survived CA 37 y

cTnlMyBPC

Arg145TrpGln998Glu

No Risk Factors

Prevention of Sudden DeathPrevention of Sudden DeathIn HCMIn HCM

35 y – Brother SD (age 39)

36 y – ICD

40 y – Generator replaced

41 y – Appropriate shock #1

50 y – Appropriate shock #2

53y – Present

5 y:

9 y:

HCM is Unpredictable

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;298:405

01234567

1 2 ≥ 3No. Risk Factors for Primary Prevention

Rat

e of

App

ropr

iate

Sho

cks

(100

per

son-

yr)

3.73.0

4.6

Overall p=0.88

33% of appropriate

shocks

Maron, BJ et. al. JAMA 2007;298:405

2.02.8 2.9

5.0

0

1

2

3

4

5

6

MassiveLVH

Family SD NSVT(Holter)

Syncope

App

ropr

iate

Sho

ck

Rat

es/Y

ear

One Risk Factor Patients With Primary Prevention


≤ 34 - 6

7 - 1011-20

21-3031-40 51-60

>90

Duration (months)

No.

Pat

ient

s

0

2

4

6

8

10

12

14

16

61-7071-90

41-50

ICD in HCM : Time to First ShockICD in HCM : Time to First Shock


High--risk

Somerisk

Cardiologist

Patient Autonomy

TRANSPARENCY / FULL DISCLOSURE / INFORMED CONSENT

?

Risk FactorsRisk FactorsPrimary Prevention Decision Tree: ICD In HCMPrimary Prevention Decision Tree: ICD In HCM

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)


Risk Stratification and Risk Stratification and ICD DecisionICD Decision--Making in HCMMaking 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

SuddenDeathRisk

SymptomProgression

End‐Stage

AF

ICD

Benign/Stable(normal longevity)


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

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.

A

RV

LV

VS

**

*

RV

VS

LV

B

Echo CMR

Maron MS et. al. in press

**

**

A B

C

73y/F 77y/M

37y/M

VS

Family T

After the Shock?

Moss et. al. MADIT-IICirculation 2004;110:3760-65

Trading SD for CHF

1

4

NYHA Class:Initial VT/VF

25

5

2 3

4

2523

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

A B

C D

VS Ao

MAC

VS

VSA

B

C

D

E

LV

RVVS

**

**

LV

RVVS

**

0

10

20

30

40

50

60

70

Alive Non-CardiacDeath

Non-HCMCardiacDeath

EmbolicStroke

HeartFailure

SCD

% o

f HC

M C

ohor

t

65%

13% 12%

2% 1%

0.2%/y

Outcome of HCM Patients First Evaluated at ≥ 60 Years Old

1%

HCM Death

Management of HCMKey Elements

Older,asymptomatic

patients

ReassuranceSurveillanceExclude HTN

Screening ofrelatives for

HCM

Avoidcompetitive

sports, volumedepletion,isometricexercise

Riskassessment

for preventionSCD

Controlexertionalsymptoms

“Meta-Analysis” of Presence DE and Adverse Cardiovascular Events

Total Events

Maron MS et al. 11 7 4

Mayo Clinic 10 10 0

Combined 21 17 4

+

LGEp-value

0.5

0.002

0.04

Foci For Ventricular Arrhythmias?

RV

LVVS

0102030405060708090

100

NSVT Couplet PVC SVT

Any DE

No DE

p<0.001p=0.001

p=0.01

p=0.06

% o

f HC

M P

atie

nts w

ith A

rrhy

thm

ia24-hour Holter Arrhythmia and Presence of DE

Adabag et. al. JACC 2008; 51:1369

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-f

ree

rate

DE (+)DE (-)

N = 202N=202

Follow-up: avg 2 years

Presence of DE vs. Events

Maron MS et. al. Circ HF 2008; 1:184

0

5

10

15

20

25

70 years 75 years 80 years 90 years

Survival to Advanced Age in HCM%

HC

M P

atie

nts

Survival Age

19%

14%

8%

2%

VS

LVAML

FW

A B

C

DE as the Only Risk Factor

Maron BJ et. al. AJC 2008; 101:544

Watkins et.al.NEJM 1992;

326:1108-14Seidman Lab

Incid

ence

of S

udde

n De

ath

per 1

000 p

erso

n -y

ears

0

2468

101214161820

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

0

2.6

7.4

11.0

18.2

Maximal LV Wall Thickness (mm)

Relation Between LV Wall Thicknessand Sudden Death in 480 HCM Patients

P= 0.001

Spirito et. al. NEJM 2000; 342:1778

… but how lowis “Low Risk”?

Bethesda Conference # 36Classification

Sports (#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

Preservationof Life

Inappropriate ShocksLead Complications (25%;5%/y)

InfectionThrombosis

Recalls

Preservationof Life

Inappropriate ShocksLead Complications (25%;5%/y)

InfectionThrombosis

Recalls

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

<1011-15

16-2021-25

26-3031-35

36-4041-45

46-5051-55

56-6061-65

66-7071-75

>76

No.

of P

atie

nts

Age At Implant (years)

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

010203040506070

Maron, BJ et. al.JAMA 2007;298:405

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

Incid

ence

of S

udde

n De

ath

per 1

000 p

erso

n -y

ears

0

2468

101214161820

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

0

2.6

7.4

11.0

18.2

Maximal LV Wall Thickness (mm)

Relation between LV Wall Thicknessand Sudden Death in 480 Patients

P= 0.001

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%

Highest

Intermediate

Lowest

ICD



Potential arbitratorsEnd-stage phaseLV apical aneurysm

Extensive delayed enhancementModifiable


Alcohol septal ablation (?)

Marked LV outflow obstruction (rest)

United StatesGermany

CanadaIreland

Denmark

Belgium

Italy

Netherlands

Australia

Austria

SwitzerlandNorway

Sweden

Finland

FranceNew Zealand

United Kingdom

Japan

SpainPortugal

Defibrillator Implants Throughout The World (per million population)

421133

104102

918786

8482

7766

54464544

4140

3327

17

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 TherapyFor Sudden Death Prevention in HCM

•ß-adrenergic blockers•verapamil

•procainamide•quinidine

•amiodarone

proarrhythmia (obsolete)

no data

efficacy?chronic use (>3y) ?

1086420

100

80

60

40

20

0

Nonobstructive

Obstructive

Years from First Gradient Measurement

Cumulative survival

in NYH

A Class I‐II (%

)

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 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.


SuddenDeathRisk

SymptomProgression

End-Stage AF

ICD

HCM (36%)

Indeterminate LVH -possible HCM (8%)

Coronary artery anomalies (17%)

Myoca

rditis (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%)


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

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

0

500

1000

1500

2000

2500

HCM

Cystic

Fibrosis

Multiple

Sclero

sisMus

cular

Dystro

phy

LQTS

Marfan ALS

Bruga

da

Atax

ia

No.

Affe

cted

/ M

illio

n“Uncommon” Diseases

Primary Prevention of Sudden Death in HCMPrimary Prevention of Sudden Death in HCM

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

Imperfect riskstratification

Perceivedliability

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

Patient autonomy

Deaths with ICDsN = 29 (6%)

• No–HCM: 14Cancer / SepsisRenal SuicideAccidentsCAD

• HCM: 14End-stageEmbolic stroke

• HCM – Arrhythmia: 1(ICD malfunction)

w

Symptom Onset (43%)

Family Screening (13%)

Routine Exam (33%)

Sports/Other Screening (4%)

Acute Event (11%)

Clinical Recognition of HCM

AdaAdabag et.al. AJC 2006;98:1507

Unpredictability

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

90

91

92

93

94

95

96

97

98

99

100

1 2 3 4 5 6 7 8 91011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859606162636465

Perc

ent L

ead

Surv

ival

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 II

After the Shock?

1

4

NYHA Class:Initial VT/VF

25

5

2 3

4

2523

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

HC(36%)

CoronaryAnomalies

(17%)

Myo

card

itis

(6%

)

AR

VC (4

%)

Ion

Chan

nel (

4%)

MVP (4

%)

LAD Bridge (3%)

CAD (3%)Aortic Rupture (3%)AS (3%)

Other† (5%)

Dilated CM (2%)

WPW (2%)

Possible HCM* ( 8%)


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

2.02.8 2.9

5.0

0

1

2

3

4

5

6

MassiveLVH

Family SD NSVT(Holter)

Syncope

App

ropr

iate

Sho

ck

Rat

es/Y

ear

One Risk FactorOne Risk Factor Patients With Primary Prevention

profiles in prognosis for hcm - osu center for continuing ... maron - scd-icd... · profiles in...

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