4.2 Heriditary Cardiomyopathies Singh

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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%



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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



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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.



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Genetic screening not recommended in:

Diagnosis of HOCM if non-diagnostic clinicalfeatures present



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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.


I IIa IIb III

I IIa IIb III


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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



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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



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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%)



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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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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



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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.



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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.



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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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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.



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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



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Thank you!

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4.2 Heriditary Cardiomyopathies Singh