Post on 05-Apr-2018
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Dhssraj Singh, MDApril 2, 2012
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Contents
Overview of inherited cardiomyopathies
Hypertrophic cardiomyopathy
Arrhythmogenic right ventricularcardiomyopathy
Non compaction cardiomyopathy
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Genetically heterogeneous set of diseasesWithin each disease there may be multiple diseasegenes
Different mutation within same gene mayproduce completely different phenotypes (eg indilated vs. hypertrophic cardiomyopathy)
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Heritable
Cardiomyopathies
HCMARVC
LVNC
Michael J. Ackerman - Genomic Advances and Retreats in Hypertrophic Cardiomyopathy
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Autosomal dominant
1:5000Unexplained hypertrophy of left ventricle,myocyte disarray, fibrosis
Often predominant involvement of LV septum
Marked phenotypical variaty due to incompletepenetrance
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Seventy percent of cases are due to sarcomeric
gene alterationsMutated genes are usually unique to familiesthat inherit the gene
Cascade family screeningDiagnostic yield of sarcomeric gene testing is60% - absence of sarcomere mutation cannotrule out familial HOCM
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Modified from Spirito P et al. NEJM336:775,1997
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MYH7-HCMCh 14q11
Beta myosin
heavy chain
~15%
MYBPC3-HCM
Ch 11p11
Myosin binding
protein C
~20%
TNNT2-HCM
Ch 1q32
Troponin T
~2%
TNNI3-HCM
Ch 19p13
Troponin I
~1%
MYL2-HCM
Ch 12q23
< 1%
MYL3-HCM
Ch 3p21
< 1%
ACTC-HCM
Ch 15q14
-actin
< 1%
TPM1-HCM
Ch 15q22.1
-tropomyosin
~1%
Michael J. Ackerman - Genomic Advances and Retreats in Hypertrophic Cardiomyopathy
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Septal Shape and Myofilament HCM
104/132 (79%)
+ve Genetic Test
15/181 (8%)
+ve Genetic Test
Binder et al. Mayo Clin Proc 81:459-467, 2006
Sigmoidal-HCM
47%
Reverse Curve-
HCM
35%
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Septal Shape and HCM Genetic Testing
79%
Reversed
41%
Neutral
30%
Apical
8%
Sigmoid
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Comprehensive or targeted (MYBPC3, MYH7,TNNI3, TNNT2) is recommended for any patient
in whom a cardiologist has established a clinicaldiagnosis of HCM based on examination ofpatients clinical history, family history andelectrocardiographic/echocardiographic
phenotypeMutation specific confirmatory testing wouldbenefit family members/relatives
2011 HRS/EHRA Expert Consensus Statement
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Mutation specific genetic testing isrecommended for first degree family members
(parents, siblings, offspring) followingidentification of HCM-causative mutation inindex case
Better than clinical screening as EKG/echo changesmay be subtle or develop late
2011 HRS/EHRA Expert Consensus Statement
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Screening gene testing for HOCM also indicatedfor:
families with history of SCD
families in which clinical diagnosis is difficult,including those with clinical complications ofHOCM despite only mild hypertrophy
Genetic analysis of post mortem specimens ininstances of sudden cardiac death where HOCMwas not previously known in family.
2011 HRS/EHRA Expert Consensus Statement
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Genetic screening not recommended in:
Diagnosis of HOCM if non-diagnostic clinicalfeatures present
2011 HRS/EHRA Expert Consensus Statement
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Developed in Collaboration with the American Association for Thoracic Surgery,
American Society of Echocardiography, American Society of Nuclear Cardiology,
Heart Failure Society of America, Heart Rhythm Society, Society for CardiovascularAngiography and Interventions, and Society of Thoracic Surgeons
American College of Cardiology Foundation and American Heart Association, Inc.
G ti T ti St t i /F il S i
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Evaluation of familial inheritance and genetic counseling is recommendedas part of the assessment of patients with HCM.
Patients who undergo genetic testing should also undergo counseling bysomeone knowledgeable in the genetics of cardiovascular disease so thatresults and their clinical significance can be appropriately reviewed with
the patient.
Screening (clinical, with or without genetic testing) is recommended infirst-degree relatives of patients with HCM.
Genetic testing for HCM and other genetic causes of unexplained cardiachypertrophy is recommended in patients with an atypical clinicalpresentation of HCM or when another genetic condition is suspected tobe the cause.
Genetic Testing Strategies/Family Screening
I IIa IIb III
I IIa IIb III
I IIa IIb III
I IIaIIb III
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Genetic testing is reasonable in the index patient tofacilitate the identification of first-degree family membersat risk for developing HCM.
The usefulness of genetic testing in the assessment of riskof SCD in HCM is uncertain.
Genetic Testing Strategies/Family Screening
I IIa IIb III
I IIa IIb III
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Genetic Testing Strategies/Family Screening
Genetic testing is not indicated in relatives when theindex patient does not have a definitive pathogenicmutation.
Ongoing clinical screening is not indicated in genotypenegative relatives in families with HCM.
I IIa IIb III
I IIa IIb III
No Benefit
No Benefit
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Genotype-Positive/Phenotype-
Negative Patients
Diagnosis
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Genotype-Positive/Phenotype-Negative Patients
In individuals with pathogenic mutations who do notexpress the HCM phenotype, it is recommended toperform serial ECG, TTE, and clinical assessment at periodicintervals (12 to 18 months in children and adolescents andabout every 5 years in adults), based on the patients age
and change in clinical status.
I IIa IIb III
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Frank J. Zimmerman, MD - Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy
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First described by Fontaine in 1977
Prevalence : 1:5000 in the US
Progressive dystrophy or cardiomyopathy of theright ventricle
Replacement of right ventricular myocardiumwith fatty tissue
may involve either/both ventricles
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Normal Myocardium
ARVD Fat Infiltration
Frank J. Zimmerman, MD - Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy
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Leads to electrical instability, ventriculararrhythmias and sudden death
Morphology may resemble DCM, but clinicallyusually presents as arrhythmia rather than HF.
ARVD/C accounts for3-4 % of SCD in young
Frank J. Zimmerman, MD - Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy
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Early concealed phase characterized bypropensity toward ventricular arrhythmia insetting of preserved morphology, histology,
ventricular function
As disease progresses, myocyte loss,inflammation fibroadiposis becomes evident.
Structural changes include regional WMA,ventricular aneurysms, increased trabeculationto global ventricular dilation and dysfunction
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Type Chromosome Gene Comment
ARVD/C 1 14q24.3 TGFb3 Progressive RV cardiomyopathy
ARVD/C 2 1q42-1q43 RyR2 ? Assoc. with CPVT
ARVD/C 3 14q11-14q12 ?
ARVD/C 4 2q32.1-q32.3 ? Localized LV involvementARVD/C 5 3p23 LAMR1 Seen in New Foundland
ARVD/C 6 10p12-14 Tyr Phos Early onset disease
ARVD/C 7 10q22 DES Assoc with myofibrillar myopathy
ARVD/C 8 6p24 Desmoplakin DSP Keratoderma and wooly hair (6-16%)
ARVD/C 9 12p11 Plakophilin PKP2 Intracellular disruption (11-43%)
ARVD/C 10 18q12.1-q12.2 Desmoglein DSG2 (10-12%)
ARVD/C 11 18q11 DesmocollinDSC2
(1-5%)
Frank J. Zimmerman, MD - Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy
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Most genes involved encode for desmosomalproteins
30 70 percent of cases harbor noted above
Once confirmed in index case, cascadescreening applied to relatives.
Failure to identify genes does not excludedisease
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Frank J. Zimmerman, MD - Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy
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Most symptoms occur in 2nd-5th decades oflife
Chest, palpitations, dizziness, syncope
First symptom may be sudden death
Subclinical form of ARVD/C in younger pts
concealed phase
Symptoms and RV cardiomyopathy
precipitated by stress or exercise
Frank J. Zimmerman, MD - Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy
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Comprehensive or targeted (DSC2, DSG2, DSP,JUP, PKP2,and TMEM43) ACM/ARVC genetictesting can be useful for patients satisfying task
force diagnostic criteria for ACM/ARVC.Genetic testing may be considered for patientswith possible ACM/ARVC (1 major or 2 minor
criteria) according to the 2010 task forcecriteria.
2011 HRS/EHRA Expert Consensus Statement
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Genetic testing is not recommended forpatients with only a single minor criterionaccording to the 2010 task force criteria.
Mutation-specific genetic testing isrecommended for family members andappropriate relatives following the identificationof the ACM/ARVC-causative mutation in an
index case.
2011 HRS/EHRA Expert Consensus Statement
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Dogged by variable penetrance, age relatedexpression, unpredictable flare ups
A family history of SCD is not necessarily a keyindicator of adverse prognosis
Unremarkable clinical evaluation does notpreclude transmission or expression of diseasein the near future
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Lead to centers offering periodic reassessmentof first, second or even third degree relatives
Prospects of lifelong screening withoutdefinitive prospect of negative reassurance maylead to anguish
Gene negative with negative clinical exams mayrarely present later with catastrophic arrest
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Michael J. Ackerman - Genomic Advances and Retreats in Hypertrophic Cardiomyopathy
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Excessive unusual trabeculations within themature left ventricle
Developmental failure of heart to fully compactthe myocardium during initial stages ofdevelopment
spongy morphological appearance of the
myocardium occurring primarily in the LV, withthe abnormal trabeculations typically beingmost evident in the apical and midlateral/-inferior portions of the LV.
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thickening of the myocardium in two distinctlayers composed of compacted and non-
compacted myocardium also classically is noted.Ratio of non-compacted versus compactedmyocardium is often larger than 2.0.
May have systolic +/- diastolic dysfunction
Associated with thromboembolism, especially inpatients with lower ejection fraction
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Disease may be seen in family members of LVNCbut also occasionally seen in relatives ofpatients with HOCM, dilated or restrictivecardiomyopathy.
May represent a spectrum of cardiomyopathybetween dilated and hypertrophic
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X linked, Autosomal dominant, autosomalrecessive or mitochondrial inheritance pattern
Sporadic in 60 70 percent.Fifteen genes have been implicated, althoughnone are predominantly involved
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LVNC genetic testing can be useful for patients in
whom a cardiologist has established a clinicaldiagnosis of LVNC based on examination of thepatients clinical history, family history, and
electrocardiographic/echocardiographicphenotype.
2011 HRS/EHRA Expert Consensus Statement
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Mutation-specific genetic testing isrecommended for family members andappropriate relatives following the identificationof an LVNC-causative mutation in the index
case.Patients with LVNC should be assessed with at leasta 3 generational family history, and all first degreerelatives of patients with LVNC should be evaluated
echocardiographicaly
2011 HRS/EHRA Expert Consensus Statement
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Thank you!