dilated cardiomyopathy

Cardiomyopathies: what are the mechanisms?

Dilated Cardiomyopathy (DCM)

Andre Keren MDAssuta Hospitals, Clalit Health

Services and Hadassah University Hospital, Israel

a malignant diseaseCM - Dilated

Clinical Presentation of DCM

• Isolated DCM/Familial DCM• DCM associated with peripheral muscle disease• DCM associated with conduction disturbances• DCM associated with multisystem disease

Elliott P, Eur Heart J 2008;29:270-276

Elliott P et al. Eur Heart J 2008;29:270-276

DCM: Prevalence• Incidence 5-8/100,000• Prevalence 1:2,700 (Olmstead County Minnesota)*• Gender (>men), Racial (>black) differences

* HCM estimated at 1:5,000

Gillum RF. (United States, 1970-1982) Am Heart J 1986;111:752-755Bagger JP et al. (Western Denmark). Br Heart J 1984;52:327-331Williams DG et al. (England). Br Heart J 1985;54:153-155Codd MB et al. (Minnesota, 1975-1984). Circulation 1989;80:564-572

DNA Mutation

Altered gene product

T-Cell activation?Autoantibodies?Cytokines

Myocarditis

Viralpersistence

DILATEDCARDIOMYOPATHY

Virus

Autoimmunity

Genetics

MyocardialMyocardialDysfunctionDysfunction

Adapted from Mestroni et al BHJ 1997;72:S35

FAMILIAL DCM (FDCM)

PREVALENCE

• 20-50% of DCM are familial & 30% of asympt fam members are clinically affected (LVE, dFS)

• 10-20% of those affected develop within 2-3 years symptomatic DCM

Michels VV-NEJM 1992; Keeling PJ- Br Heart J 1995; Gruning E-JACC 1998; Baig MK-JACC 1998; Crispell KA-JACC 1999; Mestroni L - JACC 1999.;Mahon NG Ann Int Med 2005

DCMDCMProspective Cardiovascular Prospective Cardiovascular Evaluation of Asymptomatic Evaluation of Asymptomatic

RelativesRelatives

N=767N=767

Autoimmunity in DCM

HLA DR4 MHC Class II expression Cytokines Cardiac autoantibodies Familial aggregation of autoimmune diseases

Antibodies in DCMAntibody DCM(%) Controls(%)Muscle specific

Antifibrillary 24 41Antiinterfibrillary 6 3

Cardiac specifc 26 3Antia/ß 46 0Antilaminin 78 6Antimitochondrial

M7 31 0ANT 57 0

Anti ßInhibiting 31 12Stimulating 35 0

Frequency of organ specific antibodies

Caforio ALP et al. Eur J Heart Failure 2002;4:411-417

DNA Mutation



Myocarditis

Viralpersistence


Virus

Autoimmunity

Genetics



2013 Caforio ALP et al. Eur Heart J

• The inflammation is due to infectious, toxic or an autoimmune process • The most common etiology appears to be the viral infection

Definition by the WHO/ISFC* : Inflammatory disease of the myocardium diagnosed by established histological, immunological and immunohistochemical criteria

Richardson P, McKenna WJ et al. Ciculation 1996;93:841-842

Caforio ALP et al. Eur Heart J 2013, Jul 3, ahead of print

- 129Heart 2014;9:121 Global

populationthe 2010 world caused by myocarditis in failure Heart

The burden of myocarditis as a percentage of prevalent heart failure varied by age and region from 0.5% - 4%

Kindermann I, Boehm M, et al. J Am Coll Cardiol 2012;59:779-792

Keren A, Caforio ALP. ACCA 18.10.2013

Schultz JC, Hilliard AA, Cooper LT. Mayo Clin Proc 2009;84:1001-1009

Viral infectionViral infection

myocardialmyocardialinflammationinflammation

Immune response

virus persistencevirus persistence± inflammation± inflammation

Inflammatory cardiomyopathy

virus clearance + virus clearance + inflammation inflammation (autoimmune)(autoimmune)

Genetic factors

virus clearancevirus clearanceno inflammationno inflammation

Healed myocarditis

DCM

Keren A

Caforio ALP et al. Eur Heart J 2013

Kindermann I, Boehm M et al. Circulation 2008;118:639-648

Changes in LVEF% Mortality

20% 56%

Mason JW et al. NEJM 1995

CONCLUSION: Routine immunosuppressive therapy is not indicated in histologically proven myocarditis

McCarthy RE, NEJM 2000;342:690-696; Mason JW NEJM 1995;333:269-275

Fulminant N=15, Acute N=132

93%

45%

7.8.2013

VT+ SA blocks VTs

Early +Late Arrhythmias

Mason JW N Engl J Med 1995;333:269-275; Cooper LT N Engl J Med 1997;336:1860-1866;

Kandolin R. Circ Heart Fail 2013;6:15-22

Kandolin R et al

● Gene profiling in 28 candidate genes included:Genes for cytokines, cytokine and chemokine receptors, TLR’s, apoptosis and mitochondrial respiratory chain● Gene profiling performed on 1-2 EMB’s● Patients:

Distinctive gene expression profiles in active myocarditis (MCA), cardiac sarcoidosis (CS) and idiopathic giant cell myocarditis (IGCM)

Take Home Messages GCM and CS

Gene expression profiling might be useful to overcome high sampling error due to patchy

distribution, such as giant cells

Krasniqi N, Eriksson U Eur Heart J 2014;35:2138-2139

• The first attempt to define and use “inflammatory cardiac microenvironment” for diagnostic purposes

• Possible insights into the pathogenesis of ALL inflamm CM including GCM and CS

Limitations:- Small number of pts - Highly specialized procedure- This patented gene expression needs to

be reproduced in larger studies

Caforio ALP et al. Eur Heart J 2013

ACUTE MYOCARDITIS: DIAGNOSTIC AND MANAGEMENT PROTOCOL

Clinically Suspected Myocarditis

Haemodynamically stable Preserved LV function

No eosinophiliaNo significant rhythm or

conduction disturbancesNot associated with

systemic immune disease#

History, Examination, ECG, Echo, Laboratory tests: Troponin, CRP, ESR, Blood Cell Count, BNP, Consider CMR & if Available, Serum Cardiac Autoantibodies

Consider coronary angiography and EMB

No coronary disease

General Supportive Therapy

unstable, Decreased HaemodynamicallyLV Function,

Cardiogenic Shock

Pharmacological & if needed Mechanical support ECMO, LVAD/Bi-VAD, Bridge to (

heart transplant or to recovery)

Lymphocytic Giant cell, Eosinophilic, Sarcoidosis (acute decompensation)

General Supportive Therapy Immunosuppression if unresponsive &

virus negative EMB Immunosuppression if infection negative EMB

If myocarditis is associated with systemic immune disease exacerbation, therapy overlaps with treatment of the background disease (usually #

immunosuppression). Keren A, Caforio ALP. ACCA 18.10.2013

DNA Mutation



Myocarditis

Viralpersistence


Virus

Autoimmunity

Genetics



36

Familial Genetic DCM

• 25-50% OF DCM cases• DISEASE TRANSMISSION:

- AUTOSOMAL DOMINANT - BUT also autosomal recessive, X-linked and matrilineal (mitochondrial)

• > 30 genes account for 40-50% of familial DCM

Graham RM, Owens WA. NEJM 1999;341:1759

van Spaendonck-Zwarts KY 2008; Jongbloed JD 2011; Van Tintelen JP; Cardiovasc Research 2014;101:571-578

Overlap of genes involved in different cardiomyopathies

39Seidman GS& Seidman C, Cell 2001:104:557

Figure 5. A Schematic of the Myocyte Structures that Contain Mutations (*) that Remodel the Human HeartHuman mutations in sarcomere protein are currently the only known genetic causes of hypertrophic remodeling. Mutations in proteins of the thin and thick filament of the sarcomere, cytoskeletal sarcoglycans, intermediate filament proteins, and nuclear envelope proteins can cause cardiac dilation. Genetic studies in man and model organisms indicate calcium dysregulation occurs in response to gene mutations that trigger cardiac remodeling. Calcium enters the myocyte through L-type (dihydropyridine) Ca2+ receptors to activate ryanodine receptors (RyR), thereby triggering calcium-induced calcium release (CICR). Increased calcium activates sarcomere contraction (see

40

DCMMOLECULAR MECHANISMS

• Force generation and transmission

• Decreased myocyte viability (lamins)

• Calcium cycle dysregulation (mainly through SERCA, Phospholamban and Ca binding proteins)

Dystrophin• Severe dilated cardiomyopathy • Elevated CK• Mutations in 5’ end or promoter

region of dystrophin gene cause cardiomyopathy

Muntoni, Melacini 1993, Milasin 1996

NEJM 2012;366:619

Truncated Titin mutations in DCM: the rise of a Titan- Found in 25% of familial and 18% of sporadic forms of DCM- Found in 3% of controls

RCMDCM

HCM

HCM-DCM

HCM-RCM

DCM-RCM

(MDCM)

ARVC

ARVC-DCM

(LV-ARVC)

Overlapping phenotypes

Keren A, Popp RL, Billingham M et al. Circulation 1985;72:302-309

Keren A, BillinghamME, Popp RL. J Am Soc Echo 1988;1:78-87

LVEDP 28mmHg

LVEDP 29mmHgLVEDP

26mmHg

A/C mutationLamin

Fatkin D, NEJM 1999;341:1715-1724

DCM

Atrial arrhythmias, sinus bradycardia, heart block

Sudden death

LMNA Gene Defects : Nuclear Membrane Fragmentation and Pathologic Degeneration of the AV Junction

Arbustini E et al. JACC 2002;39:981-90

Survival in Lamin A/C Mutation

75%

30%

Taylor M et al. JACC 2003;41:771-80 Familial DCM Registry Rresearch Group

KY European J Heart Fail 2013;15:628-636 Spaendonck-Zwartsvan Pinto YM, ESC Congress 2014

LMNA mutations are associated with worst survival in large cohorts of DCM

van Berlo JH, Pinto YM et al. J Mol Med 2005;83:79-83

*

…

*

Same proportion of SD in neuromuscular type (43%) as in the isolated cardiac type *(50%)

Carriers of LMNA Gene Mutations299Meta-analysis of Clinical Characteristics of

Primary prevention of sudden death in Lamin A/C gene mutations

• 19 pts with LMNA, conduction defect & LVEF 58+12% had ICD instead of pacemaker implant

• 9 of 19 (45%) received an appropriate ICD intervention for VT/VF during 39 mo’s fup

• The data suggest that these pts are at high risk of SCD before onset of clinical featured of DCM

Meune C et al. N Engl J Med. 2006; 354: 209-210

Meder B, ESC congress 2013

Risk factors- NSVT, LVEF< 45%, male (3)- Non-missense mutations (ins-del/truncating,

or mutations affecting splicing) (4).

Risk factors- NSVT, LVEF< 45%, male (3)

Risk of malignant arrhythmias in 269 LMNA mutation carriers

van Rijsingen IAW, JACC 2012;59:493-500

In pts with Lamin A/C mutations institution of early treatment including ICD is recommended

Left Ventricular ARVC (Arrhythmmogenic Cardiomyopathy - AC)

Thiene G et al. Cardiovasc Path 2005;14:165

UCLH London, UK

Naxos disease”)(“Cardiocutaneous syndromes

LEFT VENTRICULAR INVOLVEMENT IN ARVC

76% WITH LV INVOLVEMENT

Domain Binding to Desmin DesmoplakinMutation in LV ARVCCauses -

2034insA mutation

10 individuals: ARVC+LV involvement

7 Inf/Lat T wave changes

8 RBBB ventricular arrhythmia

3 exercise syncope

Norman M et al. Circulation 2005;112:636-642Norman M et al. Circulation 2005;112:636-642

Fibrofatty Replacement on LV Histology

X 10 X 20

Atlas of the clinical genetics of human dilated cardiomyopathy

Haas J et al. European Heart Journal 2015; 36:1123–1135

pts with DCM, 8 countries- 639 (46%) with known disease causing - 294

mutation

% compound or combined mutations (2)- 38 3 mutations>% - 13

In 2003 the human genome project was completed. It took 13 years, involved 20.000 researchers at a cost of $3 billions

next Using NGS, the sequencing of human genome requires a laboratory technician, generation sequencing device and about $5.000

Spaendonck-Zwarts KY EuropeanJ Heart Fail 2013;15:628-636 van

Mutations found in 20% of 418 probands with DCM evaluated by standard genotyping techniques

Haas J et al. European Heart Journal 2015; 36:1123–1135

Variant distribution in DCM genes

Conclusions

• DCM is the most common and malignant cardiomyopathy• Etiology can be genetic, infectious, autoimmune or toxic• The genetic forms represent up to 50% of cases• In virus negative inflammatory cardiomyopathy trial of immunosuppressive treatment has to be considered

dilated cardiomyopathy

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