How Hypertrophic Cardiomyopathy Became a …/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc... ·...
Transcript of How Hypertrophic Cardiomyopathy Became a …/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc... ·...
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
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
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
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
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
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
0.0
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
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%
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
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)].
≤ 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
“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
% 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%
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
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%
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
(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
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
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
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