hcm: the tip of the iceberg - monterey, ca · cancer, sepsis, renal diseases, suicide, cad,...
TRANSCRIPT
HCM Is A Global Disease
50 countries….all continents
GeneralPopulation
1:500
600,000 people in 600,000 people in U.S.U.S.
AT RISK:50,000 – 100,000 ?
Amer IndiansN=3,501;51-77 y
0.2%
CARDIAN=4,111;23-35 y
0.17%
ChinaN=8,080;18-74 y
0.16%
Rural MinnesotaN=15,137;16-87 y
0.19%
JapanN=3,354;20-77 y
0.17%
TanzaniaN=6,680;22-91 y
0.2%
HCM: The Tip Of The Iceberg
Identified
Unidentified?
w
Symptom Onset (43%)
Family Screening (13%)
Routine Exam (33%)
Sports/Other Screening (4%)
Acute Event (11%)
Clinical Recognition of HCM
Adabag et.al. AJC 2006;98:1507
HeterogeneityHeterogeneity
Asymmetrical hypertrophic cardiomyopathyAsymmetrical hypertrophy of the heartAsymmetrical septal hypertrophy Brock’s diseaseDiffuse muscular subaortic stenosisDiffuse subvalvular aortic stenosisDynamic hypertrophic subaortic stenosisDynamic muscular subaortic stenosisFamilial hypertrophic subaortic stenosisFamilial hypertrophic cardiomyopathyFamilial muscular subaortic stenosisFamilial myocardial diseaseFunctional aortic stenosisFunctional hypertrophic subaortic stenosisFunctional obstructive cardiomyopathyFunctional obstruction of the left ventricleFunctional obstructive subvalvular aortic stenosisFunctional subaortic stenosisHereditary cardiovascular dysplasiaHYPERTROPHIC CARDIOMYOPATHY (HCM)Hypertrophic constrictive cardiomyopathy) Hypertrophic hyperkinetic cardiomyopathyHypertrophic infundibular aortic stenosisHypertrophic nonobstructive cardiomyopathyHypertrophic obstructive cardiomyopathy (HOCM)Hypertrophic stenosing cardiomyopathyHypertrophic subaortic stenosis
Idiopathic hypertrophic subvalvular stenosisIdiopathic muscular hypertrophic subaortic stenosisIdiopathic muscular stenosis of the left ventricleIdiopathic myocardial hypertrophyIdiopathic stenosis of the flushing chamber of LVIdiopathic ventricular septal hypertrophyIrregular hypertrophic cardiomyopathyLeft ventricular muscular stenosisLow subvalvular aortic stenosisMuscular aortic stenosisMuscular hypertrophic stenosis of LVMuscular stenosis of the left ventricleMuscular subaortic stenosisMuscular subvalvular aortic stenosisNon-dilated cardiomyopathyNonobstructive hypertrophic cardiomyopathyObstructive cardiomyopathyObstructive hypertrophic aortic stenosisObstructive hypertrophic cardiomyopathyObstructive hypertrophic myocardiopathyObstructive myocardiopathyPseudoaortic stenosisStenosing hypertrophy of the left ventricleStenosis of the ejection chamber of LVSubaortic hypertrophic stenosisSubaortic idiopathic stenosisSubaortic muscular stenosis
27 yr/old femaleGenotyped based on +FH (MyBPC)/Phenotype (-)
33 yr/old nowand development of LVH and SAM;Phenotype (+)
Age 27y
Age 33y
Maron, BJ et. al.JACC 2001;38:315
ARV
LV
VS
*
*
*
RVVS
LV
BEcho CMR
Hypertrophic Cardiomyopathy
Sarcomeric ProteinMutations
Non-Sarcomeric Mutations
AMP-Kinase(PRKAG2)
Lamp2Lamp2(Danon)(Danon)
Storage Diseases
~ 11 Genes---or more?
> 1000 mutations
FabryDisease
Ao
LVFW
VS
A B
D
C
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Survival with HCM in an Unselected Cohortof Adults (Diagnosis > age 20)
Duration from Initial Diagnosis (years)
Cu
mu
lati
ve S
urv
ival
Rat
e
HCM
U.S. NationalHealth Statistics
n=234Avg. follow-up=8.1 yearsHCM mortality rate=1.2%/yrp=0.22
Maron BJ et al. JAMA 2008
HCM:A Bad Disease ?… Or
a Disease That Can BeBad ?
Profiles in Prognosis for HCM
SuddenDeathRisk
SymptomProgression
End-Stage
AF
Arrhythmogenic Myocardial Substrate in HCM
0
2
4
6
8
10
12
14
16
5-15 16-25 26-35 36-45 46-55 56-65 66-75 >75
Stroke
Heart Failure
Sudden
% H
CM
Mo
rtal
ity
Per
Ag
e G
rou
p
Age at Death or Most Recent Evaluation (years)
Maron, BJ et. al. Circulation 2000;102:858
HCM(36%)
CoronaryAnomalies
(17%)
Myo
card
itis
(6%
)
AR
VC
(4%
)
Ion
Cha
nnel
(4%
)
MVP
(4%
)
LAD Brid
ge (3%
)
CAD (3%)
Aortic Rupture (3%)AS (3%)
Other †(5%)
Dilated CM (2%)
WPW (2%)
Possible HCM* ( 8%
)
Sudden Death in Young Athletes
Maron, BJ et. al. Circulation 2009;119:1085-1092
Bethesda Conference # 36Recommendations
Athletes with the unequivocal diagnosis of hypertrophic cardiomyopathy should notparticipate in most competitive sports, with the possible exception of those of low intensity. This recommendation includes those athletes with or without symptoms and with or without left ventricular outflowobstruction.
HCM: identification of high risk patients
?
0.80
0.85
0.90
0.95
1.00
0 0.5 1 1.5 2 2.5 3Follow-up Duration (years)
p = 0.5
Eve
nt-
free
rat
e
DE (+)DE (-)
N = 202
N=202
Follow-up: 681 + 249 days
DE vs. Events
Highest
Intermediate
Lowest
ICD
2° preventionCardiac arrest/sustained VT
1° preventionFamilial sudden deathUnexplained syncopeMultiple-repetitive NSVT (Holter)Abnormal exercise BP response
Massive LVH
Potential arbitratorsEnd-stage phaseLV apical aneurysmMarked LV outflow obstruction (rest)Extensive delayed enhancementModifiable
Intense competitive sportsCAD
Alcohol septal ablation (?)Mutations ±
0
246
8101214
16
<15 16-19 20-24 25-29 30
Max. LV Wall Thickness (mm)
% P
atie
nts
Wit
h S
CD
Relation Between LV Thickness & SCD in 482 HCM Patients
A C
D E F
LA
P
D D
PVS
VS
B
P
D
** *
**
*
Figure 1.
Patients withLVAA(n=28)
AbortedCardiacArrest
(2)✝
ProgressiveHeart Failure/
Death(5)✝
SuddenDeath
(2)*
non-fatalembolicstroke
(1)
non-fatalembolicstroke
(1)
AppropriateICD Discharge
(3)*
Alive/Clinically
Stable(n = 16)*
AdverseEvents(n = 12)
Cardiovascular Event Rate = 11%/year
Foci For Ventricular Arrhythmias?
RV
LVVS
0102030405060708090
100
NSVT Couplet PVC SVT
Any DE
No DE
p<0.001
p=0.001
p=0.01
p=0.06
% o
f H
CM
Pat
ien
ts w
ith
Arr
hyt
hm
ia
24-hour Holter Arrhythmia and DE
VS
LVAML
FW
A B
C
DE as the Only Risk Factor
Prevention of Sudden DeathPrevention of Sudden Death
In HCMIn HCM
Amio
0
5
10
15
20
25
30
% O
n D
rug
w/ S
ud
den
Dea
th
VerapamilBeta-
Blocker Disopyramide
27%
15%17%
20%
Drugs Do Not Protect AbsolutelyFrom Sudden Death In HCM
N Engl J Med 1980;303:322.
35 y – Brother SD
36 y – ICD
40 y – Generator replaced
41 y –Appropriate
shock #1
50 y –Appropriate shock #2
52y – Present
5 y:
9 y:
HCM is Unpredictable
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Hour of Day
No.
of E
vent
s
NoonMid-night
Circadian Variability for Appropriate ICD Shocks
Maron, BJ et. al.Heart Rhythm 2009;6:599
<10
11-15
16-20
21-25
26-30
31-35
36-40
41-45
46-50
51-55
56-60
61-65
66-70
71-75
>76
No
. of P
atie
nts
Age At Implant (years)
ICD in HCM : Age at ImplantICD in HCM : Age at Implant
0
10
20
30
40
50
60
70
Maron, BJ et. al.JAMA 2007;298:40
506
103
11%
ICD in HCM: 2007ICD in HCM: 2007
5.5%/ yr
Follow-up = 3.7 ± 3 years
ICD dischargerate
Appropriate ShocksVT/VF (20%)
4%
2º prevention 1º prevention Maron, BJ et. al.JAMA 2007;298:40
High-Risk Children with HCM and ICDs
Implanted < 20 years:Appropriate shocks:Age at intervention:
Implanted < 15 years:Appropriate shocks:Age at intervention:
8323 (28%;7%/y%/y)18 + 4 years
3713 (35%;11%/y11%/y)15 + 3.6 years
0
1
2
3
4
5
6
7
1 2 ≥ 3No. Risk Factors for Primary Prevention
Rat
e of
App
ropr
iate
Sho
cks
(100
per
son-
yr)
3.7
3.0
4.6
Overall p=0.88
33% of appropriate
shocks
Maron, BJ et. al. JAMA 2007;298:40
2.0
2.8 2.9
5.0
0
1
2
3
4
5
6
MassiveLVH
Family SD NSVT(Holter)
Syncope
Ap
pro
pri
ate
Sh
ock
Rate
s/Y
ear
One Risk Factor Patients With Primary Prevention
Maron, BJ et. al. JAMA 2007;298:4
≤ 34 - 6
7 - 1011-20
21-3031-40 51-60
>90
Duration (months)
No
. Pat
ien
ts
0
2
4
6
8
10
12
14
16
61-7071-90
41-50
ICD in HCM - II: Time to First Shock
HCM—ICD Registry
29(6%)
14
14
1
Deaths
ICDMalfunction
End-stageEmbolic stroke
Cancer, sepsis,renal diseases,suicide, CAD,
accidents
No HCM
HCM
HCM-Arrhythmias
(nl EF)
Maron, BJ et. al. JAMA 2007;298:4
After the Shock?
Moss et. al. MADIT-IICirculation 2004110:3760-65
Trading SD for CHF
1
4
NYHA Class:Initial VT/VF
25
5
2 3
4
25
23
2
1
I
II
III
1
NYHA Class:At follow-up
Clinical Status Post—Appropriate ICD Shock
90%
Maron, BJ et. al. Heart Rhythm 2009; 6:993
High--risk
Somerisk
Cardiologist
Patient Autonomy
TRANSPARENCY / FULL DISCLOSURE / INFORMED CONSENT
?
Risk FactorsRisk Factors
Primary Prevention Decision Tree: ICD In HCMPrimary Prevention Decision Tree: ICD In HCM
United States
Germany
Canada
Ireland
Denmark
Belgium
Italy
Netherlands
Australia
Austria
Switzerland
Norway
Sweden
Finland
France
New Zealand
United Kingdom
Japan
Spain
Portugal
Defibrillator Implants Throughout The World (per million population)
421133
104
10291
87
8684
8277
66
54
46
4544
41
4033
27
17
Profiles in Prognosis for HCM
SuddenDeathRisk
SymptomProgression
End-Stage
AF
Beta-blocker
Verapamil
Beta-blocker
Verapamil
Verapamil+ Diuretic
Beta-blocker+ Diuretic
SubaorticObstruction
DDD Pacing
Septal Septal MyotomyMyotomy--MyectomyMyectomy
Nonobstructive
HeartTransplantation
Disopyramide
Diltiazem
Beta-blocker+ Verapamil
Management of HCMAsymptomatic
Mild-ModerateSymptoms
Severe Symptoms
? ?
Treatment Failure
RefractorySevere
Symptoms
AlcoholSeptal
Ablation
1086420
100
80
60
40
20
0
Nonobstructive
Obstructive
Years from First Gradient Measurement
Cu
mu
lati
ve s
urv
ival
in N
YH
A C
lass
I-I
I (%
)
p=0.0001RR= 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
0
50
100
150
200
250
Rest Post-Exercise
LV
Ou
tflo
w G
rad
ien
t (m
mH
g)
Ө
Ө
Maron MS, Circulation, in press, in press MS, CirculatioMaron MS, Circulation, in pressMaron, MS, Circulation, in press
Case for Septal Myectomy: The Gold Standard
• 45 years of experience
• Low operative mortality ( ≤ 1%) & virtually zero last 10 y @
major centers) --- lower than ablation
• Permanent, virtually complete reduction LVOTG to 0-10mmHg
• 85%: substantial reduction heart failure over long time
• Anatomic flexibility, under direct visualization
• Permits revision mitral / submitral anomalies
• No residual – no septal scar
• Monitor / revise resection w/ intraoperative echo
• Rapid reduction of obstruction
• Evidence of increased survival, possibly normal longevity
Surgical Septal MyectomySurgical Septal Myectomy
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
Septal Ablation: HCM
Major Issues with Alcohol Septal Ablation
• Short follow-up: Is gradient / symptom relief long-lasting?
• Residuals common –ie. PMK and ICD (20%)
• Relatively high rate of repeat procedures (25%)
• Often not successful w/ high gradients
• Dobutamine contamination of gradient data
• Myectomy after failed ablations is difficult
• The infarct/ scar and SD risk, particularly in the young
Septal Scarring
Septal ScarSeptal Scar No Scar No Scar
PostPost--ablationablation PostPost--myectomymyectomy
VS=30%VS=30%LV10%LV10%
Valeti et. al. JACC 2007;49:350
0
5
10
15
20
25
30
Sorajja Cuoco Noseberry Maron van derLee
Ventricular Tachyarrhythmias and Sudden DeathFollowing Alcohol Septal Ablation
% P
atie
nts
With
Sus
tain
ed V
T/V
F/S
D
5%7%
24% 25%
10%
SuddenDeath
Progressive Heart Failure
AF&
Stroke
End-Stage
Profiles in Prognosis for HCM
Benign/Stable(normal longevity)
Clinical Pathways of Prognosis in HCM
ICD
SDProgressive
HFEnd
Stage
AF &
Stroke
NormalLongevity
DrugsMyectomy
(alcohol ablation)
Transplant Drugswarfarin
RFA
SuddenDeathRisk
SymptomProgression
End‐Stage
AF
ICD
Benign/Stable(normal longevity)
Profiles in Prognosis for HCM
0
500
1000
1500
2000
2500
HCM
Cystic
Fibrosis
Multiple
Sclerosis
Muscular
Dystrophy
LQTS
Marfan
ALS
Brugada
Ataxia
No. A
ffected / M
illion
The“Uncommon” Diseases
Women With HCM
•Diagnosed less frequently
•Older when diagnosed (implying delay)
•More symptomatic when diagnosed
•Later recognition of symptoms
•More commonly have outflow obstruction
Olivotto et. al. JACC 2005;46:480
HCM and Race
Hospital – BasedHCM Patients(n=1,986)
Competitive Athletes:HCM-relatedSudden Death (n=102)
White(45%)
White(92%)
African-American (55%)
African-American (8%)
Bethesda Conference # 36
ClassificationSports (#8)
Consensus Panels
#2 #3 #4 #5 #6 #7
#1 #9 #10 #11 #12
Congenital Valvular
Screening / Dx
HCMOther C-M
MVPMyocarditis
Drugs
HTN
AED
CAD
Commotio Legal
Arrhythmias
(Exercise)(106; 33%)
Rest Obstruction(119; 37%)
Non-Obstructive(95; 30%)
70%
Provokable Obstruction
HCM is a Predominantly ObstructiveObstructive Disease
39Cardiac Arrest
ICD Shock
7
Died
Non-HCM (2)
End-stage (4)
SCD (1)
Survived
32
15 17
No recurrence
Recurrentcardiac arrest/
ICD shock
8 + 7 y(up to 30 y)
10 + 8 yMaron, BJ et. al.Heart Rhythm 20096:993-997
ICD in HCM
• No. Patients: 506• Centers: 42• Sites: U.S.; Italy / W.Europe;Australia• Age: 42±17 years• Gender: 64% male• LV outflow obstruction::26%• Follow-up::3.7±2.8 years• Max. LV thickness: 23± 7mm
ICD : HCM vs. CAD
CAD HCM
Implant age ~65 ~40
Risk period short long
Substrate often usually compromised intact
Intervention / yr ~30% 5%
DeathsN = 29 (6%)
• No–HCM: 14cancer / sepsisrenal suicideaccidentsCAD
• HCM: 14End-stageEmbolic stroke
• HCM – Arrhythmia: 1
(ICD malfunction)
0123456789
10
Deaths AbortedSD
FailedProcedure
App. ICDShocks
PMK MI
Short and Long-Term Outcome After Alcohol Septal Ablationfor Obstructive HCM (91 patients)
“…about one-third of HCM patients who underwent alcohol septal ablation…developed one or more cardiovascular
complications over…5.6 years”tenCate et. al.ThoraxcentrumRotterdam, The Netherlands
n=9
n=7 n=7
n=4 n=4
n=2
1086420
100
80
60
40
20
0
Nonobstructive
Obstructive
Cu
mu
lati
ve S
urv
ival
(%
)
p<0.02
Years from First Gradient Measurement
Impact of Outflow Obstruction (> 30mmHg) on Risk For Sudden Death in 1101 HCM Patients
Other Possible Contributing Risk Factors
• LV outflow obstruction
• Myocardial ischemia
• Bridged LAD
• AF
•• Alcohol Septal AblationAlcohol Septal Ablation
In Individual HCM Patients
Clinical Implications of LAMP2 Cardiomyopathy
• Survival after age 25 years unlikely
• Requires molecular diagnosis
• Deserves consideration for heart transplantation
Highest
Intermediate
Lowest
ICD
Strongest Risk Factors:Cardiac arrest
Familial SDSyncopeMultiple-repetitive NSVTBP — exerciseMassive LVH
End-Stage Apical aneurysm
Malignant genotype (?)Alcohol Ablation (?)
Septal Myectomy vs. Alcohol Septal Septal Myectomy vs. Alcohol Septal Ablation:Ablation:
Appropriate ICD ShocksAppropriate ICD Shocks
No. Pts
No. Appropriate
Shocks % %/Year
Surgical myectomy
50 6 12 2.6
Alcohol septal ablation
17 4 24 10.3
4x
pp<0.01
2.0
2.8 2.9
5.0
0
1
2
3
4
5
6
MassiveLVH
Family SD NSVT(Holter)
Syncope
Ap
pro
pri
ate
Sh
ock
Rate
s/Y
ear
One Risk FactorOne Risk Factor Patients With Primary Prevention
Electronics
Battery
Hermetic Housing
Connector
- DF Feedthrough wirePolyimide tubing
+ Backfill tube Short circuit
Joshua’s Implantable DefibrillatorPrizm 2 DR Model 1861 (10/4/01)
*Guidant aware 2002
*Manufacturing changes
1- April 2002
2- November 2002*Did not inform
physicians or patients*Continued to sell units
without the changes
during 2002
BeforeIntervention
ImmediatelyAfter
Follow-up 0
20
40
60
80
100
120
Qin JX, et al. JACC 2001;38:1994-2000.
Re
stin
g L
VO
TL
VO
TG
rad
ien
tG
rad
ien
t, m
mH
g
NS
P < 0.001
P < 0.001
Ablation
Myectomy
B.B. C.C.
D.D. E.E. F.F.
A.A.
RV
VSLV
VS
HCM:A Bad Disease ?… Or
a Disease That Can BeBad ?
35 y – Brother SD
(age 39)
36 y – ICD
40 y – Generator replaced
41 y –Appropriate
shock #1
50 y –Appropriate shock #2
5 y:
9 y:
HCM Is A Global Disease
Previously Proposed Pharmacologic TherapyFor Sudden Death Prevention in HCM
•ß-adrenergic blockers•verapamil
•procainamide•quinidine
•amiodarone
proarrhythmia (obsolete)
no data
efficacy?chronic use (>3y) ?
HCM Cohorts Annual Mortality
Tertiary–referral basedChildren 4 – 6 %Children & adults 3 – 4 %
Community–based 0.5 – 1.5 %non–tertiary regionalunselected
Non-dilated
Dilated
EndEnd--StageStage
EF < 50%
LV Cavity LV Wall
0
2
4
6
8
10
12
14
16
Death Acute MI VF PMR ICD Re-Intervention
Surgery
Ablation
% o
f P
atie
nts
0
5%
0 0
2%
14%
0
9%
0
5%
3%
9%
Serruys et al.Circulation 2005; 112: 482Rotterdam Thorax Ctr.
Myectomy Ablation
0
5
10
15
20
25
Pre Post Pre Post
16
23
1619
P < 0.05
Pe
ak O
2co
nsu
mp
tio
n
(ml/
kg/m
in)
Firoozi et al. Eur Heart J 2002;23:1617.
Amer IndiansN=3,501;51-77 y
0.2%
CARDIAN=4,111; 23-35 y
0.17%
ChinaN=8,080; 18-74 y
0.16%
Rural MinnesotaN=15,137; 16-87 y
0.19%
JapanN=3,354;20-77 y
0.17%
GeneralPopulation
1:500
500,000 people in U.S.
AT RISK:50,000 – 100,000 ?
0
500
1000
1500
2000
2500
HCM
Cystic
Fibro
sis
Mul
tiple
Scler
osis
Mus
cula
r
Dystro
phy
LQTS
Mar
fan
ALSB
ruga
da
Ata
xia
No
. A
ffe
cted
/ M
illio
n
The“Uncommon” Diseases
HCM (36%)
Indeterminate LVH -possible HCM (8%)
Coronary artery anomalies (17%)
Myo
carditi
s (6%
)
ARVC (4%)MVP (4%)
Tunneled LAD (3%)
CAD (3%)
AS (3%)
Dilated C-M (2%)
Sarcoidosis (1%)Aortic rupture (2%)Ion channelopathies
Other congenital HD Other (3%) Normal heart (3%)
Sudden Death in Young Athletes
HCM Population
Heart failuresymptoms
Drugs*
Refractorycongestivesymptoms
Genetically affected
w /o phenotype
Longitudinalfollow-up †
No / mild symptoms
(low SDrisk)
No Rx Drugs*
High risk SD ICD
AFRate-control;Cardioversion;Anti-coagulation
Non-obstructive(rest & provocation)
Obstructive(rest & / or
provocation)
Surgery:Surgery:myectomymyectomy
Surgical alternatives
DDD pacing Alcohol septalablation
Heart transplantfor “end-stage”
Bethesda Conference # 26Recommendations
Athletes with the unequivocal diagnosis of hypertrophic cardiomyopathy should notparticipate in most competitive sports, with the possible exception of those of low intensity. This recommendation includes those athletes with or without symptoms and with or without left ventricular outflowobstruction.
Asymmetrical hypertrophic cardiomyopathyAsymmetrical hypertrophy of the heartAsymmetrical septal hypertrophy Brock’s diseaseDiffuse muscular subaortic stenosisDiffuse subvalvular aortic stenosisDynamic hypertrophic subaortic stenosisDynamic muscular subaortic stenosisFamilial hypertrophic subaortic stenosisFamilial hypertrophic cardiomyopathyFamilial muscular subaortic stenosisFamilial myocardial diseaseFunctional aortic stenosisFunctional hypertrophic subaortic stenosisFunctional obstructive cardiomyopathyFunctional obstruction of the left ventricleFunctional obstructive subvalvular aortic stenosisFunctional subaortic stenosisHereditary cardiovascular dysplasiaHYPERTROPHIC CARDIOMYOPATHY (HCM)Hypertrophic constrictive cardiomyopathyHypertrophic hyperkinetic cardiomyopathyHypertrophic infundibular aortic stenosisHypertrophic nonobstructive cardiomyopathyHypertrophic obstructive cardiomyopathy (HOCM)Hypertrophic stenosing cardiomyopathyHypertrophic subaortic stenosisIdiopathic hypertrophic cardiomyopathyIdiopathic hypertrophic obstructive cardiomyopathyIdiopathic hypertrophic subaortic stenosis (IHSS)
Idiopathic hypertrophic subvalvular stenosisIdiopathic muscular hypertrophic subaortic stenosisIdiopathic muscular stenosis of the left ventricleIdiopathic myocardial hypertrophyIdiopathic stenosis of the flushing chamber of LVIdiopathic ventricular septal hypertrophyIrregular hypertrophic cardiomyopathyLeft ventricular muscular stenosisLow subvalvular aortic stenosisMuscular aortic stenosisMuscular hypertrophic stenosis of LVMuscular stenosis of the left ventricleMuscular subaortic stenosisMuscular subvalvular aortic stenosisNon-dilated cardiomyopathyNonobstructive hypertrophic cardiomyopathyObstructive cardiomyopathyObstructive hypertrophic aortic stenosisObstructive hypertrophic cardiomyopathyObstructive hypertrophic myocardiopathyObstructive myocardiopathyPseudoaortic stenosisStenosing hypertrophy of the left ventricleStenosis of the ejection chamber of LVSubaortic hypertrophic stenosisSubaortic idiopathic stenosisSubaortic muscular stenosisSubvalvular aortic stenosis of the muscular typeTeare’s disease
0
5
10
15
20
25
30
≤50 51-59 ≥60
% M
yoca
rdiu
m w
ith
DE
Ejection Fraction (%)
p<0.001
Bypass Angioplasty Bypass Angioplasty Revascularization Investigation Revascularization Investigation
(BARI)(BARI)
Theoretical Surgical Myectomy vs. Theoretical Surgical Myectomy vs. Alcohol Septal Ablation TrialAlcohol Septal Ablation Trial
25,200Patients UndergoingCoronary Angiogram
Clinically Eligible
Enrolled and Randomized
914 915
CABG PTCA
HCM Patients to be Screened
Clinically Eligible:Obstruction & SevereRefractory Symptoms
Refuse Randomization
1,200 (3.5%) Enrolled and Randomized
600 600
Myectomy ASA
2,400 Eligible for BothMyectomy and ASA
Exclusion Criteria67%
3,400 (10%)
~ 50%
4,110
12,530 (50%)
RefusedRandomization55%
Eligible for Both CABG and PTCA
Exclusion Criteria~30%
1,829 (7%)
34,000
Profiles in Prognosis for HCM
SuddenDeathRisk
SymptomProgression
End-Stage
AF
ICD
Sudden Heart Failure Stroke0
10
20
30
40
50
60
70
80
Mode of HCM Death
Ag
e a
t D
eath
(ye
ars
)
Hypertrophic Cardiomyopathy
Sarcomeric ProteinMutations
Non-Sarcomeric Mutations
AMP-Kinase(PRKAG2)
Lamp2(Danon)
Storage Diseases
~ 11 Genes---or more?
> 400 mutations
FabryDisease
Case for Septal Myectomy: The Gold Standard
• 45 years of experience
• Permanent, virtually complete reduction LVOTG to
0-10mmHg
• 85%: substantial reduction heart failure over long
time
• Permits revision mitral / submitral anomalies
• Monitor / revise resection w/ intraoperative echo
• Rapid reduction of obstruction
• Evidence of increased survival, possibly normal
longevity
Its All About Patient Selection
Myectomy
Primary optionParticularly, for younger patients w/
substantial life expectancy
Ablation
Alternative optionParticularly, poor operative candidates
significant co-morbidityadvanced agereject surgery
0
10
20
30
40
50
60
70
NYHA III/IV Post-OpRest
Gradient
Post-OpProvocable
Gradient
Late CVDeath
Failure
% o
f P
atie
nts
AblationMyectomy
59%
0%
12%
0%
6%
14%
42%
5%
15%
28%
p < 0.001
p < 0.001
p < 0.001
p < 0.001
p < 0.001
Ralph-Edwards et al.J Thorac CV Surg 2005; 129: 351
45 years 5 yr
~ 3,000 > 3,500
Surgery Ablation
Time
Cases
Ablation > Surgery by 10-35x in last 5 years
A B
C D
Ao
LVFW
VS
Case for Septal Myectomy: The Gold Standard
• 45 years of experience
• Permanent, virtually complete reduction LVOTG to
0-10mmHg
• 90%: substantial reduction heart failure over long
time
• Permits revision mitral / submitral anomalies
• Monitor / revise resection w/ intraoperative echo
• Rapid reduction of obstruction
• Low operative mortality ( ≤ 1%) & virtually zero last
12 y @ major centers) --- lower than ablation
Principles
• Patients have a fundamental right to be fully informed when they are exposed to the risk of death no matter how low that risk may be perceived.
• Patients---and their physicians---are entitled to full disclosure of product information that may affect an individual’s health or safety.
1086420
100
80
60
40
20
0
Nonobstructive
Obstructive
Cu
mu
lati
ve S
urv
ival
(%
)
p<0.02
Years from First Gradient Measurement
Impact of Outflow Obstruction (> 30mmHg) on Risk For Sudden Death in 1101 HCM Patients
0
100
200
300
400
500
600
700
800
900
Mayo Clinic ClevelandClinic
TorontoGeneral
Co
nse
cuti
ve P
ure
Mye
cto
my
Pat
ien
tsw
/o A
n O
per
ativ
e D
eath
1600
Total
1538
No Mutation
62%
MYBPC316%
MYH714%
MYL2 – 2%
TNNT2– 1.5%
TNNI3– 1%
TMP – 0.5%ACTC – 0.3%
Multiple mutations– 3%
Distribution of Disease - Causing Mutations in HCM Cohort
from Van Driest and Ackerman (Mayo); 2004
90
91
92
93
94
95
96
97
98
99
100
1 2 3 4 5 6 7 8 91011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859606162636465
Per
cen
t L
ead
Su
rviv
al
Sprint Quattro Secure model 6947
Sprint Fidelis model 6949
P=0.005
1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65
Implant Months
Obstacles From Industry
Major Issues with Alcohol Septal Ablation
• Short follow-up: Is gradient / symptom relief long-lasting?
• Residuals common –ie. PMK and ICD (20%)
• Relatively high rate of repeat procedures (25%)
• Often not successful w/ high gradients
• Myectomy after failed ablations is difficult
• Anatomic inflexibility – perforator distribution
HCM DISEASE SPECTRUM
Marked OutflowObstruction
+Severe Symptoms
(5%)
0
5
10
15
20
25
<10 11-1516-2021-2526-3031-3536-4041-4546-5051-5556-6061-6566-7071-75 >76
No
. of
Pat
ien
ts
Age At Implant (years)
ICD in HCM: Age at Implant
Major Issues: Alcohol Septal Ablation
• Short follow-up: Is gradient / symptom relief long-lasting?
• Residuals common –ie. PMK and ICD (20%)
• Anatomic inflexibility – perforator distribution / selection
• Relatively high rate of repeat procedures (25%)
• Often not successful w/ high gradients
• Dobutamine contamination of gradient data
• Myectomy after failed ablations is difficult
• The infarct/ scar and SD risk, particularly in the young
HCM Population
Heart failuresymptoms
Drugs*
Refractorycongestivesymptoms
Genetically affected
w /o phenotype
Longitudinalfollow-up †
No / mild symptoms
(low SDrisk)
No Rx Drugs*
High risk SD ICD
AFRate-control;Cardioversion;Anti-coagulation
Non-obstructive(rest & provocation)
Obstructive(rest & / or
provocation)
Surgery:Myotomy-myectomy
Surgical alternatives
DDD pacing Alcohol septalablation
Heart transplantfor “end-stage”
%
Pat
ien
ts in
Ag
e G
rou
ps
Wit
h M
ax.
LV
>3
0m
m
Age at Initial Evaluation
0
5
10
15
20
25
0-10 11-20 21-30 31-40 41-50 51-60 61-70 >70
Max. LV = 30-34mm
Max. LV 35mm
Relationship of Massive LVH to Age in HCM
Primary Prevention of SD in HC1 or 2 risk factors required?
---Individualization---
“Over-treatment” vs. “under-treatment”
Imperfect riskstratification
Perceivedliability
ICD is more powerful than our present ability to precisely identify all high risk patients
45 years 5 yr
~ 3,000 > 3,500
Surgery Ablation
Time
Cases
Ablation > Surgery by 10-35x in last 5 years
5
0.4
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 6 7 8 9 10
Years Post-op
Ove
rall
Su
rviv
al
Myectomy
Nonoperated obstructiveExpected ---U.S. population
0.5
Myectomy Enhances Long-term Survival
83%83%
61%61%
p=0.001p=0.001
0
50
100
150
200
250
Rest Post-Exercise
LV
Ou
tflo
w G
rad
ien
t (m
mH
g)
Ө
Ө
Maron MS, Circulation, in press, in press MS, CirculatioMaron MS, Circulation, in pressMaron, MS, Circulation, in pressMaron MS, Circulation, in press
Family Screening Strategies to Detect HC With Echo / ECG (Absent Genetic Testing)
•< 12 years oldoptional unless:
malignant familycompetitive athletesuspicion of early onset LVH
•12 to 18 years oldq 12 - 18 mo.
•> 18 years oldq every 5 years
(or until routine genetic testing available to resolve)
Glycogen Storage Cardiomyopathies
(mimic HCM)
PRKAG2(AMP-kinase)
• Ventricular pre-excitation
(in some)
• Range in age (31 ± 15 y)
• Relatively mild LVH
• Ventricular pre-excitation
(often)
• Young males < 25 y• Massive LVH (35 ± 15 mm)
• Tall ECG voltages
• Abnormal chemistries
ALT / CPK
Cardiac Danon(Lamp 2)
HCM Cohorts Annual Mortality
Tertiary–referral basedChildren 4 – 6 %Children & adults 3 – 4 %
Community–based 0.5 – 1.5 %non–tertiary regionalunselected
Barry J. Maron, MD
No. HCM Patients 958
• Referrals for surgical myectomy 114 (12%)
• Referred for alcohol ablation 14 (1%)
• Total Interventions (~ 9 pts / yr) 128 (13%)
Interventions for Obstructive HCMMinneapolis 1993 – 2006 (14years)
(Exercise)(106; 33%)
Rest Obstruction(119; 37%)
Non-Obstructive(95; 30%)
70%
Provokable Obstruction
Maron MS, Circulation,in press
0
20
40
60
80
100
120
5 10 15 20 25
Years From HCM Diagnosis
Per
cen
t S
urv
iva
l
HCM
Gen. Pop.HCM
P=0.20
P=0.001
Survival With HCM According to Age at Diagnosis
≥ 50 yrGen. Pop.
< 50 yr
Risk Stratification and ICD Risk Stratification and ICD DecisionDecision--Making in HCMMaking in HCM
• Current risk factors are a useful guide
• 1 risk factor can be enough (but not
obligatory for device therapy)
• Risk factors cannot be summed numerically
• ICD decisions may also be based on individualphysicianjudgment/patient autonomy considerations
Barry J. Maron, MD
No. HC Patients 725
• Referrals for surgical myectomy 20 (2.8%)
• Referred for alcohol ablation 5 (0.7%)
• Total Interventions (~ 2 pts / yr) 25 (3.5%)
Interventions for Obstructive HCMinneapolis 1993 – 2003 (10 years)
ICD in HCM
• No. Patients: 506• Centers: 42• Sites: U.S.; Italy; W.Europe;Australia• Age: 42±17 years• Gender: 64% male• LV outflow obstruction::26%• Follow-up::3.7±2.8 years• Max. LV thickness: 23± 7mm
ICD : HCM vs. CADCAD HCM
Implant age ~65 ~40
Risk period short long
Substrate often usuallycompromised intact
Intervention / yr ~30% 7%
The Oukrop Family
ICD ICD: 10/4/01
0
500
1000
1500
2000
2500
HCM
Cystic
Fibro
sis
Mul
tiple
Scler
osis
Mus
cula
r
Dystro
phy
LQTS
Mar
fan
ALSB
ruga
da
Ata
xia
No
. A
ffe
cted
/ M
illio
n
The“Uncommon” Diseases
Asymmetrical hypertrophic cardiomyopathyAsymmetrical hypertrophy of the heartAsymmetrical septal hypertrophy (ASH)Brock’s diseaseDiffuse muscular subaortic stenosisDiffuse subvalvular aortic stenosisDynamic hypertrophic subaortic stenosisDynamic muscular subaortic stenosisFamilial hypertrophic subaortic stenosisFamilial hypertrophic cardiomyopathy (FHC)Familial muscular subaortic stenosisFamilial myocardial diseaseFunctional aortic stenosisFunctional hypertrophic subaortic stenosisFunctional obstructive cardiomyopathyFunctional obstruction of the left ventricleFunctional obstructive subvalvular aortic stenosisFunctional subaortic stenosisHereditary cardiovascular dysplasiaHYPERTROPHIC CARDIOMYOPATHY (HCM)Hypertrophic constrictive cardiomyopathyHypertrophic hyperkinetic cardiomyopathyHypertrophic infundibular aortic stenosisHypertrophic nonobstructive cardiomyopathyHypertrophic obstructive cardiomyopathy (HOCM)Hypertrophic stenosing cardiomyopathyHypertrophic subaortic stenosisIdiopathic hypertrophic cardiomyopathyIdiopathic hypertrophic obstructive cardiomyopathyIdiopathic hypertrophic subaortic stenosis (IHSS)
Idiopathic hypertrophic subvalvular stenosisIdiopathic muscular hypertrophic subaortic stenosIdiopathic muscular stenosis of the left ventricleIdiopathic myocardial hypertrophyIdiopathic stenosis of the flushing chamber of LVIdiopathic ventricular septal hypertrophyIrregular hypertrophic cardiomyopathyLeft ventricular muscular stenosisLow subvalvular aortic stenosisMuscular aortic stenosisMuscular hypertrophic stenosis of LVMuscular stenosis of the left ventricleMuscular subaortic stenosis (MSS)Muscular subvalvular aortic stenosisNon-dilated cardiomyopathyNonobstructive hypertrophic cardiomyopathyObstructive cardiomyopathyObstructive hypertrophic aortic stenosisObstructive hypertrophic cardiomyopathyObstructive hypertrophic myocardiopathyObstructive myocardiopathyPseudoaortic stenosisStenosing hypertrophy of the left ventricleStenosis of the ejection chamber of LVSubaortic hypertrophic stenosisSubaortic idiopathic stenosisSubaortic muscular stenosisSubvalvular aortic stenosis of the muscular typeTeare’s disease
0
50
100
150
200
250
Rest Post-Exercise
LV
Ou
tflo
w G
rad
ien
t (m
mH
g)
Ө
Ө
Maron MS, Circulation, in press, in press MS, CirculatioMaron MS, Circulation, in pressMaron, MS, Circulation, in pressMaron MS, Circulation, in press
(Exercise)(106; 33%)
Rest Obstruction(119; 37%)
Non-Obstructive(95; 30%)
70%
Provokable Obstruction
Maron MS, Circulation,in press
Other Possible Contributing Risk Factors
•• LV outflow obstructionLV outflow obstruction
• Myocardial ischemia
• Bridged LAD
• AF
• Alcohol Septal Ablation
In Individual HCM Patients
LVLV
RVRV
LVLV
RVRV
vs vs
NYHA III; EF 40%; 30% DE NYHA I; EF 65%; 46% DE
Subsequent Events
• June: Guidant recalled 26,000 Prizm 2 DR ICDs.
• June: Guidant recalled 16,000 Contak ICDs after a patient died due to a short-circuit problem the company had identified a year earlier.
• June: Guidant recalled 21,000 AVT ICDs.
• June: Guidant recalled 46,000 Renewal ICDs.
• July: Guidant recalled 28,000 pacemakers that were prone to abrupt failure and runaway pacing that caused at least one death.
> 180,000 devices
Late Onset LVH
0
5
10
15
20
25
30
≤50 51-59 ≥60
% M
yoca
rdiu
m w
ith
DE
Ejection Fraction (%)
p<0.001
HCM and Race
Hospital – BasedHCM Patients
(n=1,986)
Competitive Athletes:HCM-related
Sudden Death (n=102)
White(45%)
White(92%)
African-American (55%)
African-American (5%)
Commercial Diagnostic Genetic Testing for HCM
• Laboratory of Molecular Medicine (Partner’s Health Care; Harvard Medical School)
• http://www.hpcgg.org/lmm
• Tests for known and novel mutations in 10 most common HCM genes
• 7 cc blood
• Results: ≤ 4 weeks
• Cost: $2800; $200 / each relative
• Limitations:- cost- false negatives
High-Risk Children with HCM and ICDs
Implanted < 20 years:Appropriate shocks:Age at intervention:
Implanted < 15 years:Appropriate shocks:Age at intervention:
8323 (28%;7%/y%/y)18 + 4 years
3713 (35%;11%/y11%/y)15 + 3.6 years
Case for Septal Myectomy: The Gold Standard
• 45 years of experience
• Low operative mortality ( ≤ 1%) & virtually zero last 12 y @
major centers) --- lower than ablation
• Permanent, virtually complete reduction LVOTG to 0-10mmHg
• 85%: substantial reduction heart failure over long time
• Anatomic flexibility, under direct visualization
• Permits revision mitral / submitral anomalies
• No residual – no septal scar
• Monitor / revise resection w/ intraoperative echo
• Rapid reduction of obstruction
• Evidence of increased survival, possibly normal longevity
Septal Myectomy vs. Alcohol Septal Septal Myectomy vs. Alcohol Septal Ablation:Ablation:
Appropriate ICD ShocksAppropriate ICD Shocks
No. Pts
No. Appropriate
Shocks % %/Year
Surgical myectomy
50 6 12 2.6
Alcohol septal ablation
17 4 24 10.3
4x
pp<0.01
Other Possible Contributing Risk Factors
• LV outflow obstruction
• Myocardial ischemia
• Bridged LAD
• AF
•• Alcohol Septal AblationAlcohol Septal Ablation
In Individual HCM Patients
Septal Scarring
Septal ScarSeptal Scar No Scar No Scar
PostPost--ablationablation PostPost--myectomymyectomy
VS=30%VS=30%LV10%LV10%
Septal Myectomy vs. Alcohol Septal Septal Myectomy vs. Alcohol Septal Ablation:Ablation:
Appropriate ICD ShocksAppropriate ICD Shocks
No. Pts
No. Appropriate
Shocks % %/Year
Surgical myectomy
50 6 12 2.6
Alcohol septal ablation
17 4 24 10.3
4x
pp<0.01
Bethesda Conference # 36
ClassificationSports (#8)
Consensus Panels
#2 #3 #4 #5 #6 #7
#1 #9 #10 #11 #12
Congenital Valvular
Screening / Dx
HCMOther C-M
MVPMyocarditis
Drugs
HTN
AED
CAD
Commotio Legal
Arrhythmias
CMR Delayed CMR Delayed Enhancement?Enhancement?
Symptom Onset (43%)
Family Screening (13%)
Routine Exam (33%)
Sports/Other Screening (4%)
Acute Event (11%)
Clinical Recognition of HCM
w
Minnesota 243 (88%)Minnesota 243 (88%) Minneapolis-St. Paul83 (30%)
N. Dakota, S. Dakota,Iowa, Wisconsin
34 (12%)
N. Dakota, S. Dakota,Iowa, Wisconsin
34 (12%)
United States
Germany
Canada
Ireland
Denmark
Belgium
Italy
Netherlands
Australia
Austria
Switzerland
Norway
Sweden
Finland
France
New Zealand
United Kingdom
Japan
Spain
Portugal
Defibrillator Implants Throughout The World - 2003(per million population)
421133
104
10291
87
8684
8277
66
54
46
4544
41
4033
27
17
Amio
0
5
10
15
20
25
30
% O
n D
rug
w/ S
ud
den
Dea
th
VerapamilBeta-
Blocker Disopyramide
27%
15%17%
20%
Drugs Do Not Protect AbsolutelyFrom Sudden DeathSudden Death In HCM