Hypertrophic Cardiomyopathy: A Contemporary And...

Barry J. Maron, MD

Director, Hypertrophic Cardiomyopathy CenterMinneapolis Heart Institute Foundation

Minneapolis, Minnesota

Disclosures:Medtronic (Grantee)GeneDx (Consultant)

Hypertrophic Cardiomyopathy:

A Contemporary

And Treatable Disease in 2015

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%

SuddenDeath

ProgressiveHeart 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-SDUnexplained syncopeMultiple-repetitive NSVT (Holter)Abnormal exercise BP responseLGE ≥ 15% of LV massMassive LVH ≥ 30 mm

Rare subgroups/potential arbitrators

End-stage (EF < 50%)LV apical aneurysmMarked LV outflow obstruction (rest)Modifiable

Intense competitive sportsCAD

LGE ≥ 15% of LV massAge ≥ 60yAlcohol 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


1°prevention



End-stage (EF < 50%)LV apical aneurysm

Marked LV outflow obstruction (rest)Modifiable


LGE ≥ 15% of LV massAge ≥ 60yAlcohol septal ablation (?)

ICD

U.S. Canada (ACC/AHA)

A C

D E F

LA

P

D D

P

VSVS

B

P

D

*

**

*

**

Figure 1.

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

Survival free from HCM related

mortality and adverse events

0.2

HCM Related Death or Adverse Clinical Events

in 70 Patients with LV Apical Aneurysms

8.1%/year

1.7%/year

Highest

Intermediate

Lowest

2°prevention


1°prevention





LGE ≥ 15% of LV massAge ≥ 60y

Alcohol septal ablation (?)

ICD

U.S./Canada: ACC/AHA

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

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


1°prevention

Family history HCM-SDUnexplained syncopeMultiple-repetitive NSVT (Holter)Abnormal exercise BP responseLGE ≥ 15% of LV mass

Massive LVH ≥ 30 mm




LGE ≥ 15% of LV mass

Age ≥ 60yAlcohol septal ablation (?)

ICD

GeneticTesting

Prognosis

HCM(w/o LVH)

HCM(w/ LVH)

To

ide

ntify

“Genotype +Phenotype - ”

Follow-up

Prevention of Sudden Death

in HCM

ICD Performance in HCM

506

103

5.5%/y

Follow-up = 3.7 ± 3 years

ICD dischargerate

AppropriateShocks (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

AppropriateAppropriateAppropriateAppropriate

ShocksShocksShocksShocks

(35%)(35%)(35%)(35%)

Highrisk

Somerisk

Cardiologist

Patient Autonomy

TRANSPARENCY / FULL DISCLOSURE / INFORMED CONSENT

?

Risk Factors

Primary Prevention Decision Tree: ICD In HCM

Evidence for Decreased HCM Mortality:

2000 Patients Presenting 10-70 years Old

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

86 ICDinterventions

% D

eath

Per

Year

1.5%/y

Maron BJ et. al.JACC 2015

Pre-ICD era

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4


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


0.8%/y

45Transplants

% D

eath

Per

Year

0.8%/y

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4


% 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


0.8%/y

30 OHCA(w/

hypothermia)% D

eath

Per

Year

0.6%/y

0.8%/y

0.5%/y

Current Mortality2015

% D

eath

Per

Year

p = 0.46

161 saved

161 saved

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

SuddenDeath

AdvancedHF

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%)

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 HCMReferral Cohorts

HCM Cohorts:Prior to utilization

of current treatmentstrategies/

interventions

ICD interventionHeart transplant/myectomy

OHCA/defibrillation/hypothermia

Present HCMCohort:

Contemporarytreatment

ICD

Sudden Death

ProgressiveHeart

Failure(obstructive)

AdvancedHeart Failure& End Stage

(non-obstructive)

AF &

Stroke


DrugsSeptal Myectomy(Alcohol Ablation)

Transplant DrugsAnticoagulants

Ablation


New HCM Paradigms:

1. Contemporary Treatable Disease

Compatible w/ Low Mortality &

Extended/Normal Longevity

2. Rx Interventions available to

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 BraunwaldEdwin C. BrockenbroughAndrew G. Morrow

Circulation, Volume XXVI, August 1962

% P

ati

en

ts W

ith

/Wit

ho

ut

ICD

In

terv

en

tio

n/S

ud

de

n D

ea

th

AppropriateICD

Intervention

No AppropriateICD

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%

161 saved

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 wall

thickness (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 tract

gradient (mm Hg)] + [0.4583082 x family history SCD] +

[0.82639195 x NSVT] + [0.71650361 x unexplained

syncope] – [0.01799934 x age at clinical evaluation (years)].

≤ 34 - 6

7 - 1011-20

21-3031-40 51-60

>90

Duration (months)

No

. P

ati

en

ts

0

2

4

6

8

10

12

14

16

61-7071-90

41-50

ICD in HCM - II: Time to First Shock

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

HCM is Unpredictable

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 MyectomyNonoperated obstructiveExpected ---US population P<0.001

83%

61%

Ommen S et. al.JACC 2006

(Operative mortality: 0.4%)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0.5%/y


Advanced Heart Failure

(n = 21)

SCD(n = 15)

% D

eath

Per

Year

Stroke (n=1)

15 SCDs but…

5 declined ICD7 pre-ICD era

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0.5%/y


Advanced Heart Failure

(n = 21)

SCD(n = 15)

% D

eath

Per

Year

Stroke (n=1)

Evidence for Decreased HCM Mortality:

2000 Patients Presenting in Mid-Life (30-59y)

MHIF/Tufts

What is Possible…..

HCM : The Tip Of The Iceberg

Identified

Unidentified

?

Unexplained LVH

Sarcomeric ProteinMutations

Non-SarcomericMutations

AMP-Kinase(PRKAG2)

Lamp2(Danon)

Storage Diseases

~ 11 Genes---or more?

> 1500 mutations

FabryDisease

HCM Is A Global Disease

50 countries….all continents

ICD in HCM for Children / Adolescents

224

43

4.4% / yr

13%/yr 3%/yr

No. Patients

Appropriate ICDDischarge (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

25-Year Contemporary Initiatives inHypertrophic Cardiomyopathy

Genetic (molecular)Single sarcomere mutation

hypothesis “Clinicians”

0 ThousandsLivesSaved

0 Many thousandsImprovedQuality of

Life

N Engl J Med 1980;303:322.

Dr. Michele Mirowski

HCM(36%)

CoronaryAnomalies

(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)

BrotherSD

(HCM)

36 504135 58 60

ICDimplant

ShockPolymorphic

VT(203/min)

VF x2shocks

(2 mo. apart)

AF*(cardioverted)

Amio200 mg

Xeralto

5 y 9 y 8 y

BD:2/19/56

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

ICDMalfunction

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


SuddenDeathRisk

SymptomProgression

End-Stage

AF

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

las

s 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

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. Patients

474 1000 428 1902

HCM Mortality

0.5%/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

14

2

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 paIents with prior alcohol septal ablaIon; with these 2 paIents 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 repair

Abbreviations:

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 HCMReferral Cohorts

HCM Cohorts:Prior to utilization

of current treatmentstrategies/

interventions

ICD interventionHeart transplant/surgical myectomy

RCA/defibrillation/hypothermia

Present HCMCohorts:

Contemporarytreatment

0

0.5

1

1.5

2

86 ICD

Interventions

45 Heart

Transplants

30 RCA (+

hypothermia)

Current

Mortality

General

Population

An

nu

al

Mo

rta

lity

(%

/ye

ar)

1.5%/y

0.8%/y

0.6%/y0.5%/y

0.8%/y

ICD

Sudden Death

ProgressiveHeart

Failure(obstructive)

AF &

Stroke


DrugsSeptal Myectomy(Alcohol Ablation)

Transplant DrugsAnticoagulants

RF Ablation


AdvancedHeart Failure& End Stage

(non-obstructive)

Highest

Intermediate

Lowest

2°prevention


1°prevention




Intense competitive sports

CADLGE ≥ 15% of LV massAge ≥ 60yAlcohol septal ablation (?)

ICD

Hypertrophic Cardiomyopathy: A Contemporary And...

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