Hypertrophic cardiomyopathy state of the art

Barry J. Maron, MD

Director, Hypertrophic Cardiomyopathy Center

Minneapolis Heart Institute Foundation

Minneapolis, Minnesota

Disclosures:

Medtronic (Grantee)

GeneDx (Consultant)

State of the Art:

Hypertrophic Cardiomyopathy

2015

New HCM Paradigms:

1. Contemporary Treatable Disease

Compatible w/ Low Mortality &

Extended/Normal Longevity

2. RX Interventions Change Clinical

Course of Disease

“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

0

5

10

15

20

25

70 years 75 years 80 years 90 years

Survival to Advanced Age in HCM: Many (Most) Patients Don’t Require Much (Anything)

% H

CM

Pati

en

ts

Survival Age

19%

14%

8%

2%

Sudden

Death Progressive

Heart Failure

AF

&

Stroke

End-

Stage

Profiles in Prognosis for HCM

Benign/Stable

(normal longevity)

HCM

(36%)

Coronary

Anomalies

(17%)

Dilated CM (2%)

Sudden Death in Young Athletes

Maron, BJ et. al.

Circulation 2009;

119:1085-1092

Prevention of Sudden Death in HCM

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

Maron BJ et. al.

JAMA 2007

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

VS

LV

A B

C

LGE as the Only Risk Factor

Maron BJ et. al.

AJC 2008; 101(4):544-7

L

G

E

LGE LGE

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

Evidence for Decreased

HCM Mortality:

1000 Patients Presenting

in Mid-Life (30-59y)

MHIF/Tufts

What is Possible…..

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

General Population "Historic Mortality"

0.8%/y

32 ICD

interventions

% D

ea

th P

er

Year

1.5%/y

Maron BJ et. al.

JACC in press

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

14

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

6 OHCA

(with

hypothermia) % D

eath

Per

Year

0.6%/y

0.8%/y

0.5%/y

Current Mortality

2014

% D

eath

Per

Year

p = 0.46

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

Sudden

Death

Advanced

HF

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

Obstruction (transplant/transplant candidates)

All HCM Patients

Current Causes of HCM Mortality (2015)

3%

(60%)

Surgical Septal Myectomy:

Quality of Life/Survival

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 Myectomy Nonoperated obstructive Expected ---US population P<0.001

83%

61%

Ommen S et. al.

JACC 2006

(Operative mortality: 0.4%)

CONTEMPORARY HCM MORTALITY

BY AGE: MHIF/Tufts

2015

<29 y 30-59 y >60 y Total

No.

Patients 474 1000 428 1902

HCM

Mortality 0.5%/y 0.5%/y 0.6%/y 0.5%/y

Estimated Decrease in

Predicted HCM Mortality

Over 50 Years

4-6%

1.5%

0.5%

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

Teare report

New disease (Braunwald; NIH)

Familial

Rare disease

“Interesting patients”

Controversy:

? Is obstruction

real

Echo Dx

↑ Recognition and

↑ risk

Common (1:500)

↑ Myectomy

Not as risky

Normal longevity

possible

Modern genetics

↓ Myectomy risk

↑ Alcohol ablation

SD prevention (ICD)

Genetic testing

Advanced imaging

Contemporary

Treatable

Disease

Phases of HCM History

• It is literally a new day… for

the HCM patients

• Maturing perceptions of

HCM and effective

treatment interventions

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

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

Profiles in Prognosis for

HCM

Sudden

Death

Risk

Symptom

Progression

End-

Stage AF

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

LA

LA

VS

RV

LV VS

A B C

D E F

Prevalence

of LGE = 55-70%

HCM is Unpredictable

Evidence for Reduced

HCM Mortality:

n=1000 Presenting 30-59y

What is possible………

Beta-

blocker Verapamil

Beta-

blocker Verapamil

Verapamil

+ Diuretic Beta-blocker

+ Diuretic

Subaortic

Obstruction DDD

Pacing

Septal

Myectomy

Nonobstructive

Heart

Transplantation

Disopyramide

Diltiazem

Beta-blocker

+ Verapamil

Management of HCM

Asymptomatic

Mild-Moderate

Symptoms

Severe

Symptoms

? ?

Treatment

Failure

Refractory

Severe

Symptoms

Alcohol

Septal

Ablation

Evidence for Reduced

HCM Mortality:

n=1000 Presenting 30-59y

What is possible………

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

D

Relation Between LV Thickness &

SCD in 482 HCM Patients

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

A C

D E F

LA

P

D D

P

VS

VS

B

P

D

* * *

* *

*

Figure 1.

0

1

2

3

4

5

6

7

1 2 ≥ 3 No. 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

% 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

Present HCM

Cohort:

Contemporary

treatment

ICD intervention

Cardiac transplant

OHCA/defibrillation/hypothermia

% P

ati

en

ts W

ith

/Wit

ho

ut

ICD

In

terv

en

tio

n/S

ud

den

Death

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%

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

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

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

D

Relation Between LV Thickness &

SCD in 482 HCM Patients

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

L

G

E

LGE LGE

Extent of LGE vs. Sudden Death Risk in HCM

Follow-up (years)

Su

rviv

al

LGE (-) LGE < 10%

LGE 10-20%

LGE > 20%

ICD Performance in HCM

506

103

5.5%/y

Follow-up =

3.7 ± 3 years

ICD discharge

rate

Appropriate

Shocks (20%)

11% 4%

2º prevention 1º prevention

VT/VF

0

1

2

3

4

5

6

7

1 2 ≥ 3 No. 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%)

Beta-

blocker Verapamil

Beta-

blocker Verapamil

Verapamil

+ Diuretic Beta-blocker

+ Diuretic

Subaortic

Obstruction DDD

Pacing

Septal

Myectomy

Nonobstructive

Heart

Transplantation

Disopyramide

Diltiazem

Beta-blocker

+ Verapamil

Management of HCM

Asymptomatic

Mild-Moderate

Symptoms

Severe

Symptoms

? ?

Treatment

Failure

Refractory

Severe

Symptoms

Alcohol

Septal

Ablation

Alcohol Septal

Ablation

Septal Scarring

Septal Scar No Scar

Post-ablation Post-myectomy

VS=30%

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

Cardiovascular Societies &

HCM Consensus Panels for

Myectomy vs. Alcohol Ablation

ACC 2003

ESC 2003

ACC 2011

AHA 2011

Myectomy

Myectomy

Myectomy

Myectomy

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

General Population "Historic Mortality"

0.8%/y

32 ICD

interventions

% D

ea

th P

er

Ye

ar

1.5%/y

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

14 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"

0.8%/y

% 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

6 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

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

% 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

Present HCM

Cohort:

Contemporary

treatment

ICD intervention

Cardiac transplant

OHCA/defibrillation/hypothermia

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

Arrhythmogenic Myocardial Substrate in HCM

HCM

(36%)

Coronary

Anomalies

(17%)

Dilated CM (2%)

Sudden Death in Young Athletes

Maron, BJ et. al.

Circulation 2009;

119:1085-1092

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

A C

D E F

LA

P

D D

P

VS

VS

B

P

D

* * *

* *

*

Figure 1.

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

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

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

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

LA

LA

VS

RV

LV VS

A B C

D E F

Prevalence

of LGE = 55-70%

L

G

E

LGE LGE

Extent of LGE vs. Sudden Death Risk in HCM

Follow-up (years)

Su

rviv

al

LGE (-) LGE < 10%

LGE 10-20%

LGE > 20%

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

(15%)

(15%)

(7%)

(7%)

(<1%)

(<1%)

(<1%)

(<1%)

(<1%)

(<1%)

Unexplained LVH

Sarcomeric Protein

Mutations Non-Sarcomeric

Mutations

AMP-Kinase

(PRKAG2)

Lamp2

(Danon)

Storage Diseases

~ 11 Genes---

or more?

> 1400 mutations

Fabry

Disease

Genetic

Testing

Prognosis

HCM

(w/o LVH)

HCM

(w/ LVH)

To

ide

ntify

“Genotype +

Phenotype - ”

Follow-up

HCM—ICD Registry

29

(6%)

14

14

1

Deaths

ICD

Malfunction End-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

Evidence for Reduced

HCM Mortality:

n=1000 Presenting 30-59y

What is possible………

Contemporary C-V treatment options

offer HC patients a reasonable

aspiration for reduced mortality and

extended longevity. The ICD has

altered clinical course affording the

possibility of normal or near normal

life expectancy.

Contemporary C-V treatment options

offer HC patients a reasonable

aspiration for reduced mortality and

extended longevity. The ICD has

altered clinical course affording the

possibility of normal or near normal

life expectancy.

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

Present HCM

Cohort:

Contemporary

treatment

ICD intervention

Heart transplant/myectomy

OHCA/defibrillation/hypothermia