Dilated cardiomyopathy pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sachin Shah, M.D., Jennifer Hall

Overview

Cardiomyopathies are defined as a heterogeneous group of diseases of the heart associated with a mechanical and/or electrical dysfunction that usually (but not always) exhibit inappropropriate ventricular hypertrophy or dilation and are due to a variety of causes that frequently are genetic.[1] Phenotypic characteristics typically include ventricular chamber enlargement and systolic dysfunction with normal wall thickness.[1] Patients with dilated cardiomyopathy may experience a progressive decline in left ventricular contractile function, ventricular and supraventricular arrhythmias, conduction system problems, thromboembolism, sudden cardiac death and/or heart failure.[1] Dilated cardiomyopathy is the third most common cause of heart failure.[1]

Pathophysiology

Genetics

Our understanding of the role of genetics in dilated cardiomyopathy continues to grow. Inherited familial dilated cardiomyopathy has been associated with 50 mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial and calcium handling proteins.[2] These mutations are listed below.

Genes Encoding Plasma Membrane Proteins

Gene Abbreviation References
Laminin alpha 4 LAMA4 [3]
Sarcoglycan delta SGCD [4][5]

Genes Encoding Cytoskeletal Proteins

Gene Abbreviation References
Actin, alpha, cardiac muscle 1 ACTC1 [6]
Actinin, alpha 2 ACTN2 [7]
Ankyrin repeat domain 1 ANKRD1

[8]

BCL2-associated athanogene 3 BAG3

[9]

Cardiotropin CTF1

[10]

Cysteine and glycine-rich protein 3 CSRP3

[7]

Desmin DES

[11] [12]

Desmoplakin DSP

[13][14][15]

DNAJ (Hsp40) homology, subfamily C, member 19 DNAJC19

[16]

Dystrophin DMD

[17][18][19][20][21][22][23]

Eyes absent homology 4 EYA4 [24]

[25]

Four and a half LIM domains 2 FHL2

[26]

Fukutin FKTN

[27]

Lysosomal-associated membrane protein 2 LAMP2

[28]

LIM domain binding 3 LDB3

[29][30][31][32]

Myosin binding protein C, cardiac MYBPC3

[33]

Myosin, heavy chain 6, cardiac muscle, alpha MYH6

[34]

Myosin, heavy chain 7, cardiac muscle, alpha MYH7

[36]

Nexilin (F actin binding protein) NEXN [37]
Presenilin 1 PSEN1

[38]

Presenilin 2 PSEN2 [38]
RNA binding motif protein 20 RBM20 [39][40]
Sarcoglycan alpha SGCD [4][5]
Sodium channel, volatage-gated, type V, alpha subunit SCN5A [32][41][42][43][44][45]
Tafazzin TAZ [46][47]
Thymopoietin TMPO [48]
Troponin C type 1 (slow) TNNC1 [49]
Troponin I type 3 (cardiac) TNNI3 [50][51]
Troponin T type 2 (cardiac) TNNT2
Tropomyosin 1 (alpha) TPM1
Titin TTN
Vinculin VCL

Genes Encoding Calcium Handling Proteins

Gene Abbreviation References
Phospholamban PLN

Genes Encoding Mitochondrial Proteins

Gene Abbreviation References
Succinate dehydrogenase complex, subunit A, flavoprotein SDHA

Genes Encoding Nuclear Proteins

Gene Abbreviation References
ATP-binding cassette, sub-family C, member 9 ABCC9
Emerin EMD
Forkhead box D4 FOXD4
Lamin A/C LMNA
Spectrin repeat containing, nuclear envelope 1 SYNE1
Spectrin repeat containing, nuclear envelope 2 SYNE2

The increase in whole exome and whole genome sequencing has significantly increased the number of rare variants that are associated with dilated cardiomyopathy [2]. A challenge in the field today is that many individuals without disease carry rare variants in their genome. Thus the task at hand is not in the sequencing but rather in the translation to define if the rare variants discovered are in fact pathophysiologic in nature. Secondly, evidence is accumulating that many patients with dilated cardiomyopathy may have many different mutations that contribute to or modify disease. [52]

Genetic Testing

Associated Conditions

A review of systems is also helpful in regards to connective tissue disease associated dilated cardiomyopathy. Some of the disease that can be associated with dilated cardiomyopathy are:

Gross Pathology

Images shown below are Courtesy of Professor Peter Anderson DVM PhD and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology

References

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  4. 4.0 4.1 {{cite journal| author=Tsubata S, Bowles KR, Vatta M, Zintz C, Titus J, Muhonen L et al.| title=Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. | journal=J Clin Invest | year= 2000 | volume= 106 | issue= 5 | pages= 655-62 | pmid=10974018 | doi=10.1172/JCI9224 | pmc=PMC381284 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10974018
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