THE CARDIOMYOPATHY CONUNDRUM

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THE CARDIOMYOPATHYCONUNDRUM
Nick Boon London February 2009
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Classification of Cardiomyopathies
Br Heart Journal 1980 48 1-18
Hypertrophic
Dilated
Restrictive
DIASTOLE
SYSTOLE
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ESC Working Group on myocardial and pericardial
disease
European Heart Journal 2008 29 270-6
Definition of cardiomyopathy A myocardial
disorder in which the heart muscle is
structurally and functionally abnormal, in the
absence of coronary artery disease, hypertension,
valvular disease and congenital heart disease
sufficient to cause the observed myocardial
abnormality.
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ESC Working Group on myocardial and pericardial
disease
European Heart Journal 2008 29 270-6
Cardiomyopathies
HCM
DCM
ARVC
Unclassified
RCM
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Hypertrophic Cardiomyopathy Dilated
Cardiomyopathy Restrictive Cardiomyopathy Amylo
id ARVD LV non-compaction
European Heart Journal 2008 29 270-6
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Hypertrophic Cardiomyopathy
inappropriate/unexplained left ventricular
hypertrophy

• Described by Donald Teare in 1958
• Autosomal dominant inheritance
• Perceived as a deadly disease of the young
• Prevalence 1 500
• Very heterogeneous - usually mild / benign

Heart 2008 94 50th anniversary issue
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Causes of Left Ventricular Hypertrophy
genetic
physiological
metabolic
Hypertension Exercise
Storage diseases Amyloid
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Genetics of Hypertrophic Cardiomyopathy

• 60 of cases have a positive family history
• Autosomal dominant with variable penetrance
• disease modifying genes
• environment
• 500 mutations affecting 12 genes now identified

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Sarcomere
Genotype does not predict Phenotype
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Asymmetrical septal hypertrophy
Bi-ventricular hypertrophy
Apical hypertrophy
End-stage dilatation
Mid-cavity obstruction
Restrictive cardiomyopathy
TnnI3 morphological heterogeneity
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Common genetic mutations in HCM

• beta- Myosin Heavy Chain mutations
• elaborate hypertrophy, ASH
• Troponin T mutations
• Modest LVH
• High risk of sudden death
• Myosin binding protein C mutations
• Onset in late adult life

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disarray
fibrosis
impression of inefficiency
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Glycogen storage disorders associated with
cardiomyopathy
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Skeletal and cardiac myopathy in AMPK disease
Hypertrophy and Glycogen accumulation

• Missense mutation of the in the gene that encodes
  the ?2 regulatory subunit of AMP-activated
  protein kinase (PRKAG2)
• Autosomal dominant
• Atrial arrthymias, pre-excitation, progressive AV
  block
• Thrombo-embolism
• gt 90 15 year survival

Arad et al 2002
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AMP kinase disease
Echocardiogram
MRI
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HCM Management Conundrums

• Diagnostic uncertainty
• Symptom control
• Optimising prognosis

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HCM Management Conundrums

• Diagnostic uncertainty
• Borderline ECG, Echo, MR

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HCM Management Conundrums

• Diagnostic uncertainty
• Borderline ECG, Echo, MR
• consistency evolution genotyping
• Other causes of LVH (hypertension physical
  training)

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HCM Management Conundrums

• Diagnostic uncertainty
• Borderline ECG, Echo, MR
• consistency evolution genotyping
• Other causes of LVH (hypertension physical
  training)
• appropriateness follow up (detraining, treatment
  of high BP) doppler studies genotyping

NB. LVH carries additional risks in all settings
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HCM Management Conundrums

• Diagnostic uncertainty
• Borderline ECG, Echo, MR
• consistency evolution genotyping
• Other causes of LVH (hypertension physical
  training)
• appropriateness follow up (detraining, treatment
  of high BP) doppler studies genotyping

NB. LVH carries additional risks in all settings
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Sudden death in young athletes
N Engl J Med 2003 349 1064-75

• Risk of sudden death during sport is not known
  but at least 1 death per year for every 200,000
  athletes lt 35 years old

Causes (387 deaths)
HCM 33 Blunt chest wall trauma 20 Coronary
artery anomalies 14 ARVD 3 DCM 2
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Athletes with marked ECG T wave abnormalities
N Engl J Med 2008 358 152-61
12,250 elite athletes screened in Italy since
1982 123 (1) had marked repolarisation ECG
abnormalities
39 had heart disease at initial evaluation 11
developed overt heart disease during f/up (mean 9
yrs) 2 sudden deaths
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HCM Management Conundrums

• Diagnostic uncertainty
• Symptom control
• effort- related SOB, chest pain, dizziness,
  syncope
• Optimising prognosis

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Dynamic LVOT obstruction in HCM
Heart 2008 94 1276-9
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Dynamic LVOT obstruction in HCM
70 HCM patients have resting or inducible LVOT
obstruction symptoms correlate closely with LVOT
Maron et al. Circulation. 2006114 2232-9. Shah
et al. Heart 2008 94 1288-94
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Treatment of LVOT obstruction in HCM

• Avoid/remove aggravating factors
• Drugs
• beta-blockers
• verapamil/diltiazem
• disopyramide
• DDD pacing
• Mitral valve replacement
• Surgical myectomy
• Septal ablation

European Heart J 2003 24 1965-1991. Heart
2008 94 1276-9
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DDD pacing in HCM
numerous positive series reports followed by 4
negative or equivocal RCTs
Jeanrenaud et al. Lancet 19923391318 European
Heart J 2003 24 1965-1991. Heart 2008 94
1276-9
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Surgical Myectomy for HCM

• 4 techniques
• Operative mortality lt 1
• Symptomatic improvement in gt 90
• Procedure-related morbidity 2-3

• Big survival benefit
• - 20 fold reduction in SCD
• - Survival rates similar to general population

JACC 2005 46 470-6 Eur Heart J 2007 28
2583-8 Heart 2008 94 1276-9
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Septal Ablation for HCM

• Introduced by Sigwart in 1994
• Technical success rates of 75-80
• Less traumatic
• Operative mortality 1.9
• CHB (Pacemaker) 9-30
• Long-term prognosis only half as good as that
  following myectomy

Heart 2008 94 1276-9
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Recommended approach to symptom control in HCM
residual symptoms especially pre-syncope
1st choice for young fit patients
best option for elderly/frail
last resort or other indication for pacing/ICD
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HCM Management Conundrums

• Diagnostic uncertainty
• Symptom control
• Optimising prognosis

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Prognosis in HCM

• Reported sudden death rate has fallen from 3-6
  per annum in 1960s to less than 1 per annum
• Better diagnosis
• Better treatment
• Some subgroups (eg.gt 40 years old, mild disease
  and no risk factors) have survival rates that are
  similar to the general population
• Death from Heart Failure and Stroke (AF) is more
  common that sudden death in elderly patients with
  HCM

Heart 2006 92 785 Heart 2008 94 1269
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Sudden death is due to VF (driven by fibre
disarray, fibrosis, autonomic dysfunction,
myocardial ischaemia and LV outflow tract
obstruction)
Strong link to exertion, often immediately after
exercise, but most deaths occur at rest
Heart 2008 94 1269
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ACC/AHA/ESC guidelines Eur Heart J 2006 27
2099-140
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Primary Prevention in HCMSt. Georges Registry
368 patients 5 Risk factors Unexplained Syncope
FHSD NSVT Abnormal exercise BP LVWT gt 30
mm
Elliott PM et al JACC 2000362212-8
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RISK
LOW
Reassure Reassess
Asymptomatic Normal exercise BP No FH SCD No
NSVT Mild LVH
ICD
HIGH
VF / or Multiple Risk Factors
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Dilated Cardiomyopathy
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Dilated Cardiomyopathy
Definition LV dilatation and systolic
dysfunction in the absence of significant
hypertension, valve disease and coronary disease
Prevalence (UK) 1 per 1000
Causes genetic autoimmunity (virus,
pregnancy) toxins (drugs, alcohol) infection
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25 of patients with dilated cardiomyopathy have
overt evidence of familial disease
225 Asymptomatic Relatives
Baig MK et al. JACC 199831195-201
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Genetics of Dilated Cardiomyopathy
Autosomal Dominant mutations in cytoskeletal,
sarcomeric, Z-band, nuclear and intercaled disc
protein genes
X-linked Muscular dystrophy (Duchenne, Becker)
Mitochondrial cytopathies
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Pathology of Dilated Cardiomyopathy
Heart 2000 83 469-74
loss of myofibrils, vacuolation, polypoid nuclei,
fibrosis
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Natural History of Dilated Cardiomyopathy
Early attrition Big improvement in last 20
years diagnosis treatment Cause specific
1981
Am J Cardiol 1981 47 525-31 Heart 2000 84
106-112
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Natural History of Dilated Cardiomyopathy
N Engl J Med 2000342 1077-84
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Natural History of Dilated CardiomyopathyRisk
Markers

• Cause
• EF at presentation
• Rate of Progression

N Engl J Med 2000342 1077-84
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Some specific forms of dilated cardiomyopathy
with a good prognosis

• Alcohol
• Peripartum
• Taku Tsubo (apical ballooning)

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Alcoholic Heart Muscle Disease

• Idiosyncratic reaction
• Male predominance
• Reversible

Am J Cardiol 1991 68 806-7
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Peripartum Cardiomyopathy

• Autoimmune myocarditis
• Risk markers Age gt30 gestational hypertension
  twins, tocolytic therapy
• LV function usully recovers but high risk of
  recurrence (especially in those with residual LV
  dysfunction)

Eur Heart J 2008 29 270-6 Lancet 2006 368
687-93 N Engl J Med 2001 344 1567-71
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Apical Ballooning Syndrome

• Middle-aged women acute emotional stress
• Presents as Ant MI (chest pain, anterior ECG
  change enzyme rise)
• Normal coronary arteries apical wall motion
  defect
• Rapid recovery good outlook

Eur Heart J 2008 29 270-6 Circulation 2005
111 472-9 N Engl J Med 2005 352 539-48
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Restrictive Cardiomyopathy

• Primary Idiopathic
• Sarcomeric protein disease
• Endomyocardial fibrosis Loefflers
• Infiltrative Amyloidosis Sarcoidosis Post-irra
  diation
• Storage Disease Haemochromatosis Glycogen
  storage disease Fabrys Disease

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AL CARDIAC AMYLOID

• Restrictive physiology
• ECG low voltage pseudoinfarct pattern
• Very poor prognosis (median survival 8.5 months
  from diagnosis lt 6/12 from onset of HF)
• Underlying (often subtle) plasma cell dyscrasia
• Non- cardiac features syncope, macroglossia,
  facial infiltration, carpal tunnel syndrome

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Arrhythmogenic RV Cardiomyopathy
Prevalence 1 in 1000 Genetics autosomal
dominant mutatations in desmosomal
proteins Diagnosis difficult Risk
stratification very imprecise
Circulation 20031083000-5 JACC 2008 52
2188-9
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ARVC Sudden Death Risk Factors

• History of cardiac arrest
• Malignant ventricular arrhythmias
• Syncope
• Extensive RV dysfunction
• LV involvement
• Younger age at time of diagnosis
• FH of SCD

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Isolated LV Non-compaction

• Disorder of endomyocardial morphogenesis
  resulting in multiple trabeculations
• Present from birth but typically presents, as
  dilated cardiomyopathy, with heart failure in
  30s and 40s
• Familial (25) male predominance
• High incidence of thrombo-embolism
• Relatively poor prognosis (80 5 year survival)

Eur Heart Journal 2005 26 187-192
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ILVNC
55

• Take home messages
• Complex, heterogeneous, unpredictable diseases
• Genetic advances have not simplified matters
  because of variable penetrance/expression
• Prognosis is often good and is improving

European Heart Journal 2008 29 270-6
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(No Transcript)
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Molecular Mechanisms of Cardiomyopathy
Final Common Pathways Cytoskeleton - Dilated
Cardiomyopathy Sarcomere Hypertrophic
Cardiomyopathy
Lancet 2002 360 654-5
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ESC Working Group on myocardial and pericardial
disease
European Heart Journal 2008 29 270-6
advantages of proposed classification

• Reflects clinical presentation
• Emphasises genetic determinants
• Encourages logical investigation
• Abandons concept of exclusion-based diagnosis

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ESC Working Group on myocardial and pericardial
disease
European Heart Journal 2008 29 270-6
limitations of proposed classification

• Different cardiomyopathies can be caused by the
  same mutation
• Multiple mutations can cause the same phenotype
• Mixed phenotypes are common

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Holter ECG recordings
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Myectomy and survival

• ICD patients at Mayo clinic 1995-2005 (4.44.1
  years from implant)
• Myectomy (n56) 0.24 p.a.
• Non-myectomy (n69) 4.3 p.a. p0.004

McLeod CJ et al. EHJ 2007282583-88
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Viral persistence
Virus
Genetics
Toxins
Autoimmunity
Myocarditis
DNA
Mutation
T-Cell activation
?Autoantibodies
Pregnancy
?Cytokines
Altered
gene
Myocardial Dysfunction
product
DILATED CARDIOMYOPATHY
Adapted from Mestroni et al BHJ 199772S35
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Restrictive Cardiomyopathy
? Sarcomeric Protein Disease
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Cardiomyopathy sources of confusion

• Terminology
• Any sort of heart muscle disease
• Primary heart muscle disease
• Primary heart muscle disease of unknown aetiology
  (diagnosis of exclusion)
• Classification
• A few phenotypes but 100s of causes
• overlap

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Old Classification of Cardiomyopathies
Circulation 1996 93 841-2 Davies M. Heart
200083469-474
Primary (Cardiomyopathy)
Secondary (Specific Cardiomyopathies)
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Survival in HCM Genotype
SCD is most common in patients with Troponin I
T mutations
Watkins H et al.1995 3321058
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CARDIAC AMYLOID

• Primary AL
• Secondary AA
• Hereditary transthyretin, fibrinogen A
• Senile - transthyretin

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Disease-Causing Mutations in Desmosomal Proteins
mostly autosomal dominant, variable penetrance,
overlap with DCM
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Intercalated disc gap junctions
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Aetiology

• 60 hypertrophic cardiomyopathies are familial
• 30-40 dilated cardiomyopathies are familial

But gene / environment interaction alcohol,
drugs, toxins, pregnancy, exercise hypertension,
infection