Barry J. Maron, MD

Hypertrophic Cardiomyopathy Institute

Tufts Medical Center

Boston, MA

Disclosures:

Medtronic (Grantee)

GeneDx (Consultant)

How Hypertrophic Cardiomyopathy

Became a Contemporary Treatable

Genetic Disease With Low Mortality

Shaped by 50 Years of Clinical Research

and Practice

First Principle:

HCM is a disease

compatible with normal

longevity without

disability or need for

intervention…

Major Treatment End-Point Pathways

% o

f P

ati

en

ts

0

10

20

30

40

50

60

56%

32%

16%

8%

Major Adverse Disease Pathways in HCM

Sudden

DeathProgressive

Heart Failure

AF

&

Stroke

End-

Stage

Profiles in Prognosis for HCM

Benign/Stable

(normal longevity)

Highest

Intermediate

Lowest

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 (?)

ICD

U.S./Canada: ACC/AHA: 2011

0

2

4

6

8

10

12

14

16

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

Max. LV Wall Thickness (mm)

% P

ati

en

ts W

ith

SC

DRelation Between LV Thickness &

SCD in 482 HCM Patients

A

RV

LV

VS

*

*

*

RV

VS

LV

B

Echo CMR

Highest

Intermediate

Lowest

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 (?)

ICD

U.S./Canada: ACC/AHA 2011

0

10

20

30

40

50

60

70

Alive Non-

Cardiac

Death

Non-HCM

Cardiac

Death

Embolic

Stroke

Heart

Failure

SCD

% o

f H

CM

Co

ho

rt

65%

13% 12%

2% 1%

0.2%/y

Outcome of HCM Patients First Evaluated ≥ 60 Years

1%

HCM Death

Aging is Good in HCM

Maron BJ et. al.

Circ 2013; 127: 585

Intermediate

Low Risk

Risk Stratification for Sudden Death in HCM

Moderate

High

No risk factors

Family history of sudden death

Nonsustained VT

Unexplained syncope

Extreme LVH

Abnormal BP response to Ex

0.5%/year

Highest

Intermediate

Lowest

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 (?)

ICD

U.S./ Canada (ACC/AHA) 2011

A C

D E F

LA

P

DD

P

VS

VS

B

P

D

** *

**

*

Figure 1.

HCM with Apical Aneurysm and Scar

1.0

0.8

0.6

0.4

0.0

0 5 1510 20

HCM patients without LV apical aneurysms

HCM patients with LV apical aneurysm

Log-rank test p<0.001

Years from First Evaluation

Su

rviva

l fre

e fro

m H

CM

re

late

d

mo

rta

lity a

nd

a

dve

rse

eve

nts

0.2

HCM Related Death or Adverse Clinical Events

in 93 Patients with LV Apical Aneurysms

8.1%/year

1.7%/year

LA

LA

VS

RV

LV VS

A B C

D E F

Prevalence

of LGE = 55-70%

L

G

E

LGELGE

Extent of LGE vs. Sudden Death Risk in HCM

Follow-up (years)

Su

rviv

al

LGE (-)LGE < 10%

LGE 10-20%

LGE > 20%

Chan RH et. al.

Circ 2014; 130(6):

484-95

Highest

Intermediate

Lowest

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 (?)

ICD

Prevention of Sudden Death

in HCM

ICD Performance in HCM

506

103

5.5%/y

Follow-up =

3.7 ± 3 years

ICD discharge

rate

Appropriate

Shocks (20%)

11%/y 4%/y

2º prevention 1º prevention

VT/VF

Maron BJ et. al.

JAMA 2007;

298:405-412

0

1

2

3

4

5

6

7

1 2 ≥ 3No. of Risk Factors for Primary Prevention

Ra

te o

f A

pp

rop

ria

te In

terv

en

tio

ns

pe

r 1

00

pe

rso

n-y

r

3.8

3.0

4.1

Overall p=0.88

Appropriate

Shocks

(35%)

High

risk

Some

risk

Cardiologist

Patient

Autonomy

TRANSPARENCY / FULL DISCLOSURE / INFORMED CONSENT

?

Risk Factors

Primary Prevention Decision Tree: ICD In HCM

NEW PARADIGM IN

HYPERTROPHIC

CARDIOMYOPATHY

Evidence for Decreased

HCM Mortality:

2000 Patients Presenting

10-70 years Old

Tufts Medical Center

What is Possible…..and

Role of HCM Centers

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

General Population "Historic Mortality"

0.8%/y

86 ICD

interventions

% D

eath

Per

Year

1.5%/y

Maron BJ et. al.

JACC in press

Pre-ICD era

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

General Population "Historic Mortality"

0.8%/y

% D

eath

Per

Year

0.8%/y

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

General Population "Historic Mortality"

0.8%/y

45

Transplants

% D

eath

Per

Year

0.8%/y

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

General Population "Historic Mortality"

% D

eath

Per

Year

0.8%/y

0.6%/y

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

General Population "Historic Mortality"

0.8%/y

30 OHCA

(w/

hypothermia)% D

eath

Per

Year

0.6%/y

0.8%/y

0.5%/y

Current Mortality

2014

% D

eath

Per

Year

p = 0.46

161 lives saved

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0.5%/y

Current Mortality

2014

Advanced

Heart Failure

(n = 21)

SCD

(n = 15)

% D

eath

Per

Year

Stroke (n=1)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0.5%/y

Current Mortality

2014

Advanced

Heart Failure

(n = 21)

SCD

(n = 15)

% D

eath

Per

Year

Stroke (n=1)

15 SCDs but…

5 declined ICD

7 pre-ICD era

0

0.1

0.2

0.3

0.4

0.5

0.6

≤ 29 30-59 ≥ 60

(n = 474) (n = 1000) (n = 428)

Age in Years—Initial Evaluation

HC

M-R

ela

ted

Mo

rtali

ty

0.500.54

0.60

Sudden

Death

Advanced

HF

Paradigm Change in Causes of Death: Advanced Heart Failure w/o

Obstruction (transplant/transplant candidates)

All HCMPatients

Current Causes ofHCM Mortality (2015)

3%

(60%)

Surgical Myectomy: Quality of Life/Survival

Reversal Form of HF

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

Major Surgical Myectomy Centers 2000-2016

(North America)

• Center No. Myectomy Mort.

• Mayo 1525 0.3%

• Cleveland 1550 0.4%

• Tufts 425 0.9%

• Toronto 315 0.6%

• NYU 185 0.6%

• 4000 0.4%

WHO SHOULD DO IT?

(Operative Mortality)

• Community Hospitals

8%

• HCM Centers

0.4%

•

Non-

ObstructiveRest

Obstruction

Provocable

Obstruction

249 104220No. 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

Relation of Progressive Heart Failure to Outflow Obstruction

• ITS PROBABLY

BETTER TO BE

NONOBSTRUCTIVE

…..UNLESS YOU GET

REALLY SICK

0

0.5

1

1.5

2

% H

CM

Mo

rta

lity

HCM-Related Mortality

0

0.5

1.5

1

6

General U.S.

Population

0.8%/y

0.5%/y

1.5%/y

3-6%/y

Early HCM

Referral Cohorts

HCM Cohorts:

Prior to utilization

of current treatment

strategies/

interventions

ICD intervention

Heart transplant/myectomy

OHCA/defibrillation/hypothermia

Present HCM

Cohort:

Contemporary

treatment

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

ICD

Sudden

Death

Progressive

Heart

Failure

(obstructive)

Advanced

Heart Failure

& End Stage

(non-

obstructive)

AF

&

Stroke

Benign/Stable(normal longevity)

Drugs

Septal Myectomy

(Alcohol Ablation)

Transplant Drugs

Anticoagulants

Ablation

Profiles in Prognosis for HCM

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

0

5

10

15

20

25

70 years 75 years 80 years 90 years

Survival to Advanced Age in HC%

HC

M P

ati

en

ts

Survival Age

19%

14%

8%

2%

The ESC-HCM prediction formula for SD is as follows:

Probability SCD at 5 years = 1 – 0.998 exp (Prognostic index);

where Prognostic index = [0.15939858 x maximal LV wallthickness (mm)] – [0.00294271 x LV maximal wall thick-ness2 (mm2)] + [0.0259082 x left atrial diameter (mm)] +[0.00446131 x maximal (rest/Valsalva) LV outflow tractgradient (mm Hg)] + [0.4583082 x family history SCD] +[0.82639195 x NSVT] + [0.71650361 x unexplainedsyncope] – [0.01799934 x age at clinical evaluation (years)].

HCM is Unpredictable

≤ 3

4 - 6

7 - 10

11-20

21-30

31-40 51-60

>90

Duration (months)

No

. P

ati

en

ts

0

2

4

6

8

10

12

14

16

61-70

71-90

41-50

ICD in HCM: Time to First Shock

Maron BJ et. al. JAMA 2007;298:405-412

161 saved

“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

VS

LV

A B

C

LGE as the Only Risk Factor

% P

ati

en

ts W

ith

/Wit

ho

ut

ICD

In

terv

en

tio

n/S

ud

den

De

ath

Appropriate

ICD

Intervention

No Appropriate

ICD

Intervention

ESC Risk Score

<4%<4% 4-6%4-6% >6%>6%

Risk/5y Risk/5y

<4% 4-6% >6%

Risk/5y

Sudden Death

Assessment of ESC Sudden Death Risk Score

(n = 1649)

60%

26%

63%

9%

0

10

20

30

40

50

60

0 1 2 3

% o

f P

ati

en

ts

No. of End-Point Pathways

56%

33%

9%

1%

1 Adverse Pathway

718 146AF

Outcome

6

19

121

476

Pathway End-Point

Death – HCM

Survived

21

52

403

96

26

1

69

Death – non-HCM

Death – HCM

Survived

Death – non-HCM

Death – HCM

Survived

Death – non-HCM

204(9%)

154

38

12

HF + SD

2 Adverse Pathways

37

109

8 Death - HCM

Survived

Death - non-HCM

1

9

2 Death - HCM

Survived

Death - non-HCM

4

24

10 Death - HCM

Survived

Death - non-HCM

0 57

2 y

HCM

Diagnosis

(SD in 2

brothers)

4645

#1

45

ICD

implant

50 5149 52 53 5554

#2 #3

50

Heart

failure

#4 #5/6

52

Myectomy

#7 #8 #9

Asymptomatic

ICD interventions

27(1%)

3 Adverse Pathways

7

Died

20

Survived

NYHA

I/II = 16

III = 4

6

1

HCM-related

Non-

HCM-related

100

80

60

40

20

00 2 4 6 8 10

Pro

po

rtio

n o

f P

ati

en

ts S

urv

ivin

g

Time (years)

Pathway = 0

Pathway = 1

Pathway = 2

Pathway = 3

1.1 %/year

1.2 %/yearp=0.38

2.4 %/year

Patients with

LVAA

(n=28)

Aborted

Cardiac

Arrest

(2)✝

Progressive

Heart Failure/

Death

(5)✝

Sudden

Death

(2)*

non-fatal

embolic

stroke

(1)

non-fatal

embolic

stroke

(1)

Appropriate

ICD Discharge

(3)*

Alive/

Clinically

Stable

(n = 16)*

Adverse

Events

(n = 12)

Cardiovascular Event Rate = 11%/year

ICD in HCM for Children / Adolescents

224

43

4.4% / yr

13%/yr 3%/yr

No. Patients

Appropriate ICD

Discharge (19%)

2° prevention 1° prevention

Follow-up=

4.3 ± 3.3 yr

Initial shock 9-23 y

(mean= 17 y)

Maron BJ et. al.

JACC 2013;

61:1527-35

≤ 3

4 - 6

7 - 10

11-20

21-30

31-40 51-60

>90

Duration (months)

No

. P

ati

en

ts

0

2

4

6

8

10

12

14

16

61-70

71-90

41-50

ICD in HCM - II: Time to First Shock

Maron BJ et. al. JAMA 2007;298:405-412

HCM is Unpredictable

Profiles in Prognosis for

HCM

Sudden

Death

Risk

Symptom

Progression

End-

StageAF

General

Population

1:500

700,000 people

in 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%

LA

LA

VS

RV

LV VS

A B C

D E F

Prevalence

of LGE = 55-70%

Genetic

Testing

Prognosis

HCM

(w/o LVH)

HCM

(w/ LVH)

To

ide

ntify

“Genotype +

Phenotype - ”

Follow-up

Evidence for Decreased

HCM Mortality:

2000 Patients Presenting

in Mid-Life (30-59y)

MHIF/Tufts

What is Possible…..

Unexplained LVH

Sarcomeric Protein

MutationsNon-Sarcomeric

Mutations

AMP-Kinase

(PRKAG2)

Lamp2

(Danon)

Storage Diseases

~ 11 Genes---

or more?

> 1500 mutations

Fabry

Disease

HCM Is A Global Disease

50 countries….all continents

N Engl J Med 1980;303:322.

Dr. Michele Mirowski

HCM

(36%)

Coronary

Anomalies

(17%)

Dilated CM (2%)

Sudden Death in Young Athletes

Maron, BJ et. al.

Circulation 2009;

119:1085-1092

K.K. 23 Years with ICD and HCM

* preceded by asymptomatic

AF on ICD (3 weeks)

Brother

SD

(HCM)

36 504135 58 60

ICD

implant

Shock

Polymorphic

VT

(203/min)

VF x2

shocks

(2 mo. apart)

AF*

(cardioverted)

Amio

200 mg

Xeralto

5 y 9 y 8 y

BD:

2/19/56

25-Year Contemporary Initiatives in

Hypertrophic Cardiomyopathy

Genetic (molecular)

Single sarcomere mutation

hypothesis “Clinicians”

0 ThousandsLives

Saved

0 Many thousandsImproved

Quality of

Life

Septal Scarring

Septal Scar No Scar

Post-ablation Post-myectomy

VS=30%

LV 10%Valeti et. al. JACC 2007;49:350

VS

LV

A B

C

LGE as the Only Risk Factor

Maron BJ et. al.

AJC 2008; 101(4):544-7

HCM—ICD Registry

29

(6%)

14

14

1

Deaths

ICD

MalfunctionEnd-stage

Embolic stroke

Cancer, sepsis,

renal diseases,

suicide, CAD,

accidents

No HCM

HCM

HCM-Arrhythmias

(nl EF)

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

1086420

100

80

60

40

20

0

Nonobstructive

Obstructive

Years from First Gradient Measurement

Cu

mu

lati

ve

su

rviv

al

in N

YH

A C

lass I-I

I (%

)

p=0.0001

RR= 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

Cardiovascular Societies &

HCM Consensus Panels for

Myectomy vs. Alcohol Ablation

ACC 2003

ESC 2003

ACC 2011

AHA 2011

Myectomy

Myectomy

Myectomy

Myectomy

HCM : The Tip Of The Iceberg

Identified

Unidentified

?

0

500

1000

1500

2000

2500

No. A

ffe

cte

d / M

illio

nThe“Uncommon” Diseases

CONTEMPORARY HCM MORTALITY

BY AGE: MHIF/Tufts

2015

<29 y 30-59 y >60 y Total

No.

Patients474 1000 428 1902

HCM

Mortality0.5%/y 0.5%/y 0.6%/y 0.5%/y

70HCM patients

with LV Apical

Aneurysms

11 Deaths

18Alive with HCM

Events

HCM related

death/event rate=

8.1% / year

5

HF

Death

2

SCD

4

Non-

cardiac

1

42

Transplant

listing

2

Transplant

3

Thrombo-

embolic

event

ICD

interventions

41Alive without

Events

2

OOHCA

1Thromboembolic

event 6 years prior

to death

Apical thrombus identified

without thromboembolic history

9

Clinical Course in 70 HCM Patients with

LV Apical Aneurysms

Operative Deaths**

Institution No. Myectomies Age (years) % Male No. %

Mayo Clinic (Rochester, MN) 1411 51 14 55 4† 0.3

Cleveland Clinic 1470Δ 55 14 55 6 0.4

Tufts Medical Center‡ (Boston) 348 52 15 56 4 1.1

Toronto General 306 49 13 62 2 0.6

Mount Sinai-St. Luke’s (NYC) 160 53 ± 14 48 1 0.6

Totals 3,695 54 14 55 17 0.4

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 yearsΔ includes 19% of patients with mitral valve repairAbbreviations:MN = Minnesota; NYC = New York City

Operative Mortality Associated with Septal Myectomy* at North American Hypertrophic Cardiomyopathy Centers, 2000-2014

HCM is Unpredictable

(15%)

(15%)

(7%)

(7%)

(<1%)

(<1%)

(<1%)

(<1%)

(<1%)

(<1%)

0

0.5

1

1.5

2

% H

CM

Mo

rta

lity

HCM-Related Mortality

0

0.5

1.5

1

6

General U.S.

Population

0.8%/y

0.5%/y

1.5%/y

3-6%/y

Early HCM

Referral Cohorts

HCM Cohorts:

Prior to utilization

of current treatment

strategies/

interventions

ICD intervention

Heart transplant/surgical myectomy

RCA/defibrillation/hypothermia

Present HCM

Cohorts:

Contemporary

treatment

Highest

Intermediate

Lowest

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 (?)

ICD

0

0.5

1

1.5

2

86 ICDInterventions

45 HeartTransplants

30 RCA (+hypothermia)

CurrentMortality

GeneralPopulation

An

nu

al M

ort

alit

y (%

/ye

ar)

1.5%/y

0.8%/y

0.6%/y0.5%/y

0.8%/y

ICD

Sudden

Death

Progressive

Heart

Failure

(obstructive)

AF

&

Stroke

Benign/Stable(normal longevity)

Drugs

Septal Myectomy

(Alcohol Ablation)

Transplant Drugs

Anticoagulants

RF Ablation

Profiles in Prognosis for HCM

Advanced

Heart Failure

& End Stage

(non-

obstructive)