1. MOGE(S) or Clinical-genetic Classification of Cardiomyopathy

2. The Term “Idiopathic” in the Process of Eradication

Jagat Narula MD PHD MACC

Mount Sinai Heart

NO DISCLOSURES

1. PLEASE, IT IS NOT pVMc-CM 2. TIME TO TREAT THE FAMILY

Arbustini, Narula et al. JACC 2013

Ever-Expanding Pool of Genetic CM

~100 genes are confirmed and the NGS is expected to further increase the knowledge.

– Based on the underlying gene mutations numerous new terms (such as desmosomalo-, cytoskeletalo-, sarcomyo-, channelo-, dystrophino-, or lamino-pathies) are being proposed that are likely to cloud the CM description, and it is important that a uniform nomenclature is developed.

Is the CM Management Strategy Archaic?

Although the diagnosis based on phenotype is still clinically useful it is not sufficient to define prognosis. Major clinical decisions (such as ICD) are taken based on functional (such as LVEF in DCM) or morphological (such as LVWT in HCM) criteria regardless of the risk of genetic defect.

– Troponinopathies may not show severe LVWT but carry a high arrhythmogenic potential. Laminopathies may not show severe LV dysfunction when the arrhythmia first strikes. Dystrophinopathies may show dramatically enlarged and dysfunctional LV but carry least risk of arrhythmias, but may deteriorate rather precipitously with small insult such as a flu.

SECONDARY CARDIOMYOPATHIES

(Syestemic diseases involving heart)

AHA and Barry Maron Made a Valiant Attempt in 2006 All Cardiomyopathies ARE Genetic in Origin…

ESC Retains a Status-Quo in 2008 Phenotype MUST Supersede Genotype…

Arbustini, Narula et al. JACC 2014

JUST BELIEVE IN IT!

DCM AD AVB, >sCPK LMNA p.Arg190Trp

IS IT ALL ABOUT GETTING USED TO IT?

+ .

I:1 I:2

II:1 II:2 II:3 II:4

I:1 I:2

II:1 II:2 II:3 II:5 II:4

III:1

HTx

HTx HF HF HTx

EF 55%

LVEDD 41mm

ECG AVB

sCPK 110mU/mL

NYHA IV

DES

Gly84Ser

Onset: 35 years

JACC November 18, 2013

GLOBAL HEART November 19, 2013

JACC July 22, 2014

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http://moges.biomeris.com

TNM STAGING

yT4(m) N0(i+) M1b G3 LVI+ R2

y denotes that the patient has received neoadjuvant therapy prior to resection,p presents pathological stage after resectionT4 is the extent of tumor, multiple residual tumor nodules in different lobes of ipsilateral lung,N - nodal status [N0(i+)] isolated tumor cells only in negative lymph node or N0, andM represents metastases where M1b means distant metastases [in contrast to M1a which is thoracic metastases such as C/L lung, pleural nodules or malignant pleural/pericardial effusion].G in this staging is histologic grade [1 = well; 2 = moderate; 3 = poorly differentiated],LVI + represents lymphovascular invasion [LVI-, absent], andR is residual disease after treatment [R0 = no residual disease; R1 = microscopic residual disease; R2 = grossly identified residual disease].

Howsoever complex it may sound, oncologists are expected to use standard TNM staging. TNM nosology is constantly expanding, is very flexible, but ensures completeness.Simply looking at [ypT4(m) N0(i+) M1b G3 LVI+ R2] offers all information about the patient.

However, in the common practice this patient is considered to be suffering from Lung Cancer.

M O G E S

ENDORSED BY THE WORLD HEART FEDERATION

Arbustini, Narula et al. JACC 2014

ME(H) OH GAD EG-MYH7 [R663H] SA-I

ME(H) OH GAD EG-NA SA-I

M0(H) OO GAD EG-MYH7 [R663H] SA-I

M O G E S

MH OH GAD EG-MYH7 [R663H] SB-I

H H AD G MYH7[R663H] B I

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A family with HCM

I:2 MYBPC3 F247C

Mild LVH Death: trauma: 84 years

II:6 II:3 Onset: 42 years

Last control: 71 years

EF:53% - ICD - AF MYH7 R663H

MYBPC3 F247C

I:1 MYH7 R663H

HCM onset: 42 years SD: 76 years

II:2 Onset: 59 years

Last control: 68 years MYBPC3

IVS7-3C>T IVS = 12 mm

II:7 Onset:32 years

Last control: 59 years EF:53% - ICD MYH7 R663H MYBPC3 -/-

III:1 Onset: 36 years

Last control: 42 years ECHO: negative

MYBPC3 IVS7-3C>T

III:2 Onset:20 years Last control: 37 years EF:69% - ICD MYH7 R663H MYBPC3 IVS7-3C>T MYBPC3 F247C

III:3 MYH7 R663H

III:4 MYH7 R663H

III:5 MYH7 -/-

III:6 MYH7 -/-

II:4 64 years Healthy

No Genetic

Test

II:5 62 years Healthy

No Genetic

Test

c

II:1 74 years

HCM MYH7 R663H

MYBPC3 -/-

IV:1 Age: 2 years MYH7 R663H + MYBPC3 F247C

I I I

I I

I

1 2

1 2 3 4

1 2 3 4 5 6

IVS

PP

LVEDD

EF

IVS

PP

LVEDD

EF

15 mm

6 mm

70 mm

25%

11 mm

9 mm

48 mm

58%

10 mm

10 mm

52 mm

69%

12 mm

12 mm

50 mm

62%

10 mm

9 mm

40 mm

66%

I6 mm

6 mm

72 mm

20%

IVS

PP

LVEDD

EF

IVS

PP

LVEDD

EF

IVS

PP

LVEDD

EF

IVS

PP

LVEDD

EF

II:1 and II:2 MH+D OH GAD EG-MYBPC3[p.(Asp228Asn)]+MTDNA MT-T1[A4300G] SC-IV

+ +

+ + + + + + - +

+ + - + +

Yet Another family with HCM

MOGE(S) in a Family with AFD

MH OH+K GX-L EG.GLA+

Age: 62 years Stroke at 59 years

55 years GI Problems

42 years Renal Failure

27 years Asymptomatic Incidental diagnosis of LVH (ECG and Echo) PR Interval = 116

Tracing medical reports No cardiac information

Dialysis for 9 years Death at 55 years

No autopsy/genetic test

87 years Arterial Hypertension

PR Interval = 120 Intermittent proteinuria

GLA -/-

GLA +/-

GLA +

IV:1

ECG PR= 112 msec IVS = 9mm

Angiokeratomas Renal function = normal

Cornea Verticillata ECG PR = 122 IVS = 11 mm Renal function = normal

Angiokeratomas GLA +

GLA +/-

C

MOGE(S) in DCM: Dystrophinopathy

Low tachyarrythmic risk even with severe LV dilatation and dysfunction

M0 OH+M+sCPK GX-LR EG-DYS(del 45-48)+

I I I

I I

I

I:1 I:2

II:1 II:2 II:3 II:4

III:1 IiI:2 III:3 III:4 III:5 III:6

III:7

.

MD[AVB] OH GAD EG-LMNA[Leu197Pro fsX2] SC-II

ME(D) OH GAD EG-LMNA[Leu197Pro fsX2] SA-I

MU(D) O0 GAD EG-LMNA[Leu197Pro fsX2] SA-I

I I I

I I

I

I:1 I:2

II:1 II:2 II:3 II:4

III:1 III:2 III:3 III:4 III:5

MOGE(S) in DCM: Cardiolaminopathy

Non-amyloid pure RCM: Sarcomeric genes

Troponinopathies

TNNI3, TNNT2

Markers

ECG: no AVB

LV thickness: normal

Restrictive pattern

Dilated atria

Mismatch:

Myocyte hypertrophy: absent

Disarray: present

Natural history

Diagnosis later than HCM

Malignant: HTx

High arrhythmogenic risk: ICD

Heart. 2008 Oct;94(10):1257.

Heart. 2008;94:1257.

ETIOLOGY, LEFT BOX G Genetic cause G-OC Obligate carrier G-ONC Obligate non-carrier G-DN De novo G-Neg Genetic test negative for the known family mutation G-0 No genetic test, any reason G-A Genetic, amyloidosis G-HFE Genetic, hemochromatosis G-HES Genetic, hypereosinophilic synd

ETIOLOGY, LEFT BOX NG Genetic defect not identified/ non-genetic etiology NG-T Toxic/degenerative NG-M Inflammatory/myocarditis infectious/non-infectious NG-AI Auto-immune, inflammatory NG-Hs Hypersensitivity, inflammatory NG-A Amyloidosis, type NG-Eo Eosinophilic disease NG-O Other causes

CONCLUSIONS

We have proposed a descriptive nosology that combines morpho-functional trait and organ/system involvement with familial inheritance pattern, identified genetic defect or other etiologies. As for the universal TNM staging for the tumors, it is expected that this description will be improved, revised, modified and made more comprehensive and user friendly. It will allow better understanding of the disease, easier communication among physicians and help develop multi-center/multi-national registries to promote research in diagnosis and management of cardiomyopathies.

JACC November 18, 2013

GLOBAL HEART November 19, 2013

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or, http://moges.biomeris.com