©2013 MFMER |

Sudden Cardiac Death in HCM Evidence and Uncertainties

Banff 2014

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©2013 MFMER |

Epidemiology of HCM-Related Mortality

• 774 pt

• MN & Italy

Maron: Circ, 2000

In bed (16%) Moderate-

severe exertion (16%)

Sedentary/mild

exertion (68%)

Mild (class II)

(32%)

Asymptomatic (39%)

Severe (class III)

(29%)

Clinical Profile of SCD

0

1

2

3

4

5

5-15 16-25 26-35 36-45 45-55 56-65 66-75 >75Age at initial evaluation (years)

Pt

(%)

Annual HCM-Related Mortality

Mode of death Sudden Heart failure Stroke All HCM related

3329123-9

©2013 MFMER |

Routine Device Interrogation Event 2 mo previously – pt unaware of any discharges

3270206-28

©2013 MFMER |

0

40

80

120

160

200

47-Year-Old Female with Angina and HCM No Prior History of Syncope

Vaglio: Nat Clin Prac CV Med, 2005

16:10:00-1

16:10:15-1

16:10:30-1

16:10:45-1

Heart rate

8 10 12 14 16 18 20 22 0 2 4 6 8 10 12

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©2013 MFMER |

Electrophysiologic Characteristics of Sustained VT/VF in HCM

• 68 pt

• ICD

• SMVT – 5 pt (47 episodes) VFib – 4 pt (1 episode/pt)

• Average time to 1st shock – 1.9 yr (3 days-5.9 yr)

Cha: JCE, 2007

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Clinical Profile

• Clustering 3 pt

7 episodes – 44 min

4 episodes – 5 min

25 episodes – 2 hr

• Initiating rhythm – sinus tachycardia or AFib 5/9 pt and 43/51 episodes

©2014 MFMER |

• 46-year-old male

• Asymptomatic from a cardiovascular standpoint .

• Played high school sports (including football) without incident

• Strong family Hx of HCM with SCD age 15 in one nephew and ICD implants with appropriate discharges and in his brother and one niece

• Told 2 years previously that he does not have the disease

3319219-3

©2014 MFMER |

ECG-Normal

Echo

• Mildly increased septal thickness (14 mm) with mildly abnormal strain in basal septal area

MRI

“No MR findings for obstructive cardiomyopathy. Minimal increased thickness of basal and mid septum (13-14 mm.)relative to remaining segments. No areas of fibrosis/delayed enhancement.”

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©2014 MFMER |

Call from patient – “You saved my life”

Reply – “Guess I did”

3319219-13

©2013 MFMER |

SCD in HCM – Potential Pathophysiologic Substrates and Clinical Risk Factors

Ommen and Gersh EHJ, 2009

NSVT • Rest • Exercise

Severity of LVH

Abnormal exercise blood pressure response Unexplained syncope

Family history of SCD

Role of isolated myofilament mutations

Outflow

Fibrosis, scar Myocardial disarray

Independent CAD

Obstruction Gradient

Autonomic instability

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SCD in Hypertrophic Cardiomyopathy

The dilemma

Risk stratification

• Imprecise

• Low PPV

• Heterogeneity within

each risk factor,

eg, FHx

• Inappropriate – 23%

shocks

• Infection – 3.8%

• Lead problems – 6.7%

• Psychologic trauma

Lin: Heart, 2009 Maron: JAMA, 2007 O’Mahony: Heart, 2011

Complications – 36%

Therapy – ICD

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Survival of Family Members According to Mutation

Watkins: NEJM, 1992

0

20

40

60

80

100

0 20 40 60 80

Age (year)

Cu

mu

lati

ve

su

rviv

al

(%) Val606Met

Arg249GIn

Arg453Cys

Arg403GIns

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©2013 MFMER |

Genetics of HCM – Changing Concepts

Van Driest: JACC, 2002; Van Driest: Circ, 2002; Van Driest: Mayo Clin Proc, 2005

• Sarcomeric mutations in <50% of pt

?

Novel genetic substrates

• Specific mutations (benign/malignant) are rare and unreliable estimates of risk

?

• Novel genetic/environmental modifiers

• Impact of genetic substrate on SCD is small

• There are no genetic specific phenotypes

?

Novel genetic/environmental modifiers

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Role of FH of SCD as a Risk Factor

Is FH alone –

without other risk factors

A risk factor for SCD

3270206-38

?

©2013 MFMER |

F.H. of SCD and ICD Discharges

• 177 pts

• 4-6 year follow-up

• F.H. of SCD without other risks factors

Bos AJC, 2010

0

1

2

3

4

5

One RF

(only

FH-SD)

One RF

(other than

FH-SD)

Multiple

RF

including

FH-SD

Multiple

RF

without

FH-SD

Annual risk of SCD in HCM

Rate

of

ap

pro

pri

ate

dis

ch

arg

e

ICD

dis

ch

arg

e (

per

100 p

ers

on

-years

)

P=0.8

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©2014 MFMER |

Indications for ICD Placement ACC/AHA Guidelines 2011

3329372-14

Gersh et al: Cric, 2011

Prior cardiac arrest

or sustained VT

Family history-SD in

first-degree relative or

LV wall thickness 30 mm or

recent unexplained syncope

Nonsustained VT or

abnormal BP response

ICD not recommended

ICD recommended

ICD reasonable

ICD can be useful

Role of ICD uncertain

Other SCD risk

modifiers* present?

Yes

No

Yes

Yes

Yes

No

No

No Class I

Class IIa

Class IIb

Class III

Legend

*Severe untreated obstruction

Late Gadalinium enhancement

Apical aneurysm

Genetic testing?

©2014 MFMER |

0

100

200

300

HC

M c

ohort

(%

)

0

Risk Factors for SCD

1 2 3

217

149

49 13

Sudden Cardiac Death in Patients Presenting at Age 60 Years

Maron: Circ, 2013

3333043-19

HCM deaths/events)

0

20

40

60

HC

M c

ohort

(%

)

Survivors Non-

cardiac

death

Non-HCM

cardiac

death

Embolic

stroke‡

Heart

failure*

SD†

Outcomes

‡AFib 3/6 *1 cardiac transplant †3 pt aborted VT/VF

65

13 12 1.4 0.7 1.2

0.24%/yr 0.12%/yr 0.20%/yr

©2013 MFMER |

Proposed ESC Guidelines for Prevention

3312742-17

Elliott P: ESC Congress, 2014

History

2-D/Doppler Echo

48-hr ambulatory ECG

• Age • FHx of sudden cardiac death • Unexplained syncope • LV outflow gradient • Maximum LV wall thickness • Left atrial diameter* • NSVT

HCM-risk score

Low risk

5-yr risk <4%

Intermediate risk

5-yr risk ≥4-<6%

High risk

5-yr risk ≥6%

ICD in general

not indicated

ICD may be

considered IIB

ICD should be

considered IIA

©2013 MFMER |

Anatomic Consequences of Myectomy and Ablation-MRI Study

Valeti: JACC, 2007

Surgical septal myectomy – 34 patients

Alcohol septal ablation – 45 patients

Resected tissue 2.71.4% of LV mass

Range 0.8-5.9

Infarcted tissue 83% of LV mass Range 3.6-13.6

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©2013 MFMER |

Rates of Sustained VT/VFib or Appropriate ICD Discharges

*1° and 2° prevention **2.8% in pt without SCD risk factors

Pt/

yr

(%)

ICD Registry (Maron 2007)

Composite (4 series)

Ten Cate (2010)

Cuoco (2008)

Noseworthy (2009)

Mayo (McLeod

EHJ 2007)

ICD Registry Alcohol Septal Ablation Myectomy

Secondary prevention

Primary prevention

**

* 0.2

3312742-19

©2013 MFMER |

Alcohol Septal Ablation Outcomes Multicenter North American Registry – 874 Patients

Nagueh: JACC, 2011

89

8 3

0

73

23

3.9 0.65

0

20

40

60

80

100

1 2 3 4

Class

Pt

(%)

CCS class angina

NYHA class dyspnea

Symptomatic status (776±26 days)

3270206-19

©2013 MFMER |

Alcohol Septal Ablation Outcomes Multicenter North American Registry – 874 Patients

Nagueh: JACC, 2011

89

8 3

0

73

23

3.9 0.65

0

20

40

60

80

100

1 2 3 4

Class

Pt

(%)

CCS class angina

NYHA class dyspnea

Symptomatic status (776±26 days)

“Average annual rate of ventricular tachycardia/ventricular

fibrillation was 3.9%/year. ICD discharges – 1.2%/year.”

3270206-19

©2013 MFMER |

Survival After Ablation Mean Follow-Up 5-7 Years

Mayo Clinic 177 Patients

• Age 65 years mean (26-80 yrs)

• Women – 68%

• NYHA class 3-4 dyspnea – 100%

Sorajja et al: Circ, 2012

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Follow-up (years)

%

Myectomy – age and gender-matched

Ablation

Expected

79%

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©2014 MFMER |

• Establishing the cause of HCM

• Defining the link between genotype and phenotype

• Management and evaluation of genotype positive/ phenotype negative relatives

• Clinical significance of myocardial fibrosis

• Therapies to directly modify the pathophysiology

• Refining risk stratification for SCD

• Therapies to treat and prevent AF and its associated risks

• Comparative assessment of septal reduction strategies

Hypertrophic Cardiomyopathy – Future Research Needs

Mutation positive

Mutation negative

Gersh et al: Guidelines, 2011

3327355-2

©2014 MFMER |

• Establishing the cause of HCM

• Defining the link between genotype and phenotype

• Management and evaluation of genotype positive/ phenotype negative relatives

• Clinical significance of myocardial fibrosis

• Therapies to directly modify the pathophysiology

• Refining risk stratification for SCD

• Therapies to treat and prevent AF and its associated risks

• Comparative assessment of septal reduction strategies

Hypertrophic Cardiomyopathy – Future Research Needs

Mutation positive

Mutation negative

Gersh et al: Guidelines, 2011

Refining risk stratification for SCD

3327355-2

©2013 MFMER |

SCD in HCM

50 Years of Progress

“We now know much

more about what we

do not know.”

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