Dilated cardiomyopathy pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Dilated cardiomyopathy}}
{{Dilated cardiomyopathy}}


{{CMG}}; '''Associate Editor-in-Chief:''' Sachin Shah, M.D., Jennifer Hall  
{{CMG}}; '''Associate Editor-in-Chief:''' Sachin Shah, M.D., Jennifer Hall


==Overview==
==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]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al.| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref> Phenotypic characteristics typically include [[ventricular chamber enlargement]] and [[systolic dysfunction]] with normal [[wall thickness]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al.| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref> 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]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al.| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref> Dilated cardiomyopathy is the third most common cause of [[heart failure]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref>
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]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al.| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref> Phenotypic characteristics typically include [[ventricular chamber enlargement]] and [[systolic dysfunction]] with normal [[wall thickness]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al.| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref> 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]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al.| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref> Dilated cardiomyopathy is the third most common cause of [[heart failure]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref>


==Pathophysiology==
==Pathophysiology==
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===Genetics===
===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.<ref name="pmid23281406">{{cite journal| author=McNally EM, Golbus JR, Puckelwartz MJ| title=Genetic mutations and mechanisms in dilated cardiomyopathy. | journal=J Clin Invest | year= 2013 | volume= 123 | issue= 1 | pages= 19-26 | pmid=23281406 | doi=10.1172/JCI62862 | pmc=PMC3533274 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23281406 }} </ref> These mutations are listed below.
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.<ref name="pmid23281406">{{cite journal| author=McNally EM, Golbus JR, Puckelwartz MJ| title=Genetic mutations and mechanisms in dilated cardiomyopathy. | journal=J Clin Invest | year= 2013 | volume= 123 | issue= 1 | pages= 19-26 | pmid=23281406 | doi=10.1172/JCI62862 | pmc=PMC3533274 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23281406 }} </ref> These mutations are listed below.


====Genes Encoding Plasma Membrane Proteins====
====Genes Encoding Plasma Membrane Proteins====
{| class="wikitable" border="1" style="background:FloralWhite"
{| class="wikitable" border="1" style="background:FloralWhite"
|Gene||Abbreviation||References||
|-
| style="background: #efefef; width:50%" | '''Gene'''
| style="background: #efefef; width:20%" | '''Abbreviation'''
| style="background: #efefef; width:20%" | '''References'''
|-
|-
| [[Laminin alpha 4]]|| [[LAMA4]] ||<ref name="pmid17646580">{{cite journal| author=Knöll R, Postel R, Wang J, Krätzner R, Hennecke G, Vacaru AM et al.| title=Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. | journal=Circulation | year= 2007 | volume= 116 | issue= 5 | pages= 515-25 | pmid=17646580 | doi=10.1161/CIRCULATIONAHA.107.689984 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17646580 }} </ref>
| [[Laminin alpha 4]]|| [[LAMA4]] ||<ref name="pmid17646580">{{cite journal| author=Knöll R, Postel R, Wang J, Krätzner R, Hennecke G, Vacaru AM et al.| title=Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. | journal=Circulation | year= 2007 | volume= 116 | issue= 5 | pages= 515-25 | pmid=17646580 | doi=10.1161/CIRCULATIONAHA.107.689984 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17646580 }} </ref>
|-
|-
| [[Sarcoglycan delta]]|| [[SGCD]]||<ref name="pmid10974018">{{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 </ref> <ref name="pmid18285821">{{cite journal| author=Trabelsi M, Kavian N, Daoud F, Commere V, Deburgrave N, Beugnet C et al.| title=Revised spectrum of mutations in sarcoglycanopathies. | journal=Eur J Hum Genet | year= 2008 | volume= 16 | issue= 7 | pages= 793-803 | pmid=18285821 | doi=10.1038/ejhg.2008.9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18285821 }} </ref>
| [[Sarcoglycan delta]]|| [[SGCD]]||<ref name="pmid10974018">{{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 </ref><ref name="pmid18285821">{{cite journal| author=Trabelsi M, Kavian N, Daoud F, Commere V, Deburgrave N, Beugnet C et al.| title=Revised spectrum of mutations in sarcoglycanopathies. | journal=Eur J Hum Genet | year= 2008 | volume= 16 | issue= 7 | pages= 793-803 | pmid=18285821 | doi=10.1038/ejhg.2008.9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18285821 }} </ref>
}
|-
|}


====Genes Encoding Cytoskeletal Proteins====
====Genes Encoding Cytoskeletal Proteins====
{| class="wikitable" border="1" style="background:FloralWhite"
{| class="wikitable" border="1" style="background:FloralWhite"
|Gene||Abbreviation||References||
|-
|-
|{[[Actin, alpha, cardiac muscle 1]]|| [[ACTC1]]||<ref name="pmid9563954">{{cite journal| author=Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT| title=Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. | journal=Science | year= 1998 | volume= 280 | issue= 5364 | pages= 750-2 | pmid=9563954 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9563954 }} </ref>
| style="background: #efefef; width:50%" | '''Gene'''
| style="background: #efefef; width:20%" | '''Abbreviation'''
| style="background: #efefef; width:20%" | '''References'''
|-
| [[Actin, alpha, cardiac muscle 1]] || [[ACTC1]] || <ref name="pmid9563954">{{cite journal| author=Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT| title=Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. | journal=Science | year= 1998 | volume= 280 | issue= 5364 | pages= 750-2 | pmid=9563954 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9563954 }} </ref>
|-
| [[Actinin, alpha 2]] || [[ACTN2]] || <ref name="pmid14567970">{{cite journal| author=Mohapatra B, Jimenez S, Lin JH, Bowles KR, Coveler KJ, Marx JG et al.| title=Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. | journal=Mol Genet Metab | year= 2003 | volume= 80 | issue= 1-2 | pages= 207-15 | pmid=14567970 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14567970 }} </ref>
|-
| [[Ankyrin repeat domain 1]] || [[ANKRD1]] ||
|-
| [[BCL2-associated athanogene 3]] || [[BAG3]] ||
|-
| [[Cardiotropin]] || [[CTF1]] ||
|-
| [[Cysteine and glycine-rich protein 3]] || [[CSRP3]] ||
|-
| [[Desmin]] || [[DES]] ||
|-
| [[Desmocollin 2]] || [[DSC2]] ||
|-
| [[Desmoplakin]] || [[DSP]] ||
|-
| [[DNAJ (Hsp40) homology, subfamily C, member 19]] || [[DNAJC19]] ||
|-
| [[Dystrophin]] || [[DMD]] ||
|-
| [[Eyes absent homology 4]] || [[EYA4]] ||
|-
| [[Four and a half LIM domains 2]] || [[FHL2]] ||
|-
| [[Fukutin]] || [[FKTN]] ||
|-
| [[Lysosomal-associated membrane protein 2]] || [[LAMP2]] ||
|-
| [[LIM domain binding 3]] || [[LDB3]] ||
|-
| [[Myosin binding protein C, cardiac]] || [[MYBPC3]] ||
|-
| [[Myosin, heavy chain 6, cardiac muscle, alpha]] || [[MYH6]] ||
|-
| [[Myosin, heavy chain 7, cardiac muscle, alpha]] || [[MYH7]] ||
|-
| [[Nexilin (F actin binding protein)]] || [[NEXN]] ||
|-
| [[Presenilin 1]] || [[PSEN1]] ||
|-
| [[Presenilin 2]] || [[PSEN2]] ||
|-
|-
||[[Actinin, alpha 2]]|| [[ACTN2]]||<ref name="pmid14567970">{{cite journal| author=Mohapatra B, Jimenez S, Lin JH, Bowles KR, Coveler KJ, Marx JG et al.| title=Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. | journal=Mol Genet Metab | year= 2003 | volume= 80 | issue= 1-2 | pages= 207-15 | pmid=14567970 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14567970 }} </ref>
| [[RNA binding motif protein 20]] || [[RBM20]] ||
|-
|-
||[[Ankyrin repeat domain 1]|| [[ANKRD1]]
| [[Sarcoglycan alpha]] || [[SGCD]] ||
**[[BCL2-associated athanogene 3]], [[BAG3]]
|-
**[[Cardiotropin]], [[CTF1]]
| [[Sodium channel, volatage-gated, type V, alpha subunit]] || [[SCN5A]] ||
**[[Cysteine and glycine-rich protein 3]], [[CSRP3]]
|-
**[[Desmin]], [[DES]]
| [[Tafazzin]] || [[TAZ]] ||
**[Desmocollin 2]], [[DSC2]]
|-
**[[Desmoplakin]], [[DSP]]
| [[Titin-cap]] || [[TCAP]] ||
**[[DNAJ (Hsp40) homology, subfamily C, member 19]], [[DNAJC19]]
|-
**[[Dystrophin]], [[DMD]]
| [[Thymopoietin]] || [[TMPO]] ||
**[[Eyes absent homology 4]],[[EYA4]]
|-
{{col-break|width=33%}}
| [[Troponin C type 1 (slow)]] || [[TNNC1]] ||
**[[Four and a half LIM domains 2]], [[FHL2]]
|-
**[[Fukutin]], [[FKTN]]
| [[Troponin I type 3 (cardiac)]] || [[TNNI3]] ||
**[[Lysosomal-associated membrane protein 2]], [[LAMP2]]
|-
**[[LIM domain binding 3]], [[LDB3]]
| [[Troponin T type 2 (cardiac)]] || [[TNNT2]] ||
**[[Myosin binding protein C, cardiac]], [[MYBPC3]]
|-
**[[Myosin, heavy chain 6, cardiac muscle, alpha]], [[MYH6]]
| [[Tropomyosin 1 (alpha)]] || [[TPM1]] ||
**[[Myosin, heavy chain 6, cardiac muscle, alpha]], [[MYH7]]
|-
**[[Nexilin (F actin binding protein]], [[NEXN]]
| [[Titin]] || [[TTN]] ||
**[[Presenilin 1]], [[PSEN1]]
|-
**[[Presenilin 2]], [[PSEN2]]
| [[Vinculin]] || [[VCL]] ||
{{col-break|width=33%}}
|-
**[[RNA binding motif protein 20]], [[RBM20]]
|}
**[[Sarcoglycan alpha]], [[SGCD]]
**[[Sodium channel, volatage-gated, type V, alpha subunit]], [[SCN5A]]
**[[Tafazzin]], [[TAZ]]
**[[Titin-cap]], [[TCAP]]
**[[Thymopoietin]], [[TMPO]]
**[[Troponin C type 1 (slow)]], [[TNNC1]]
**[[Troponin I type 3 (cardiac)]],[[TNNI3]]
**[[Troponin T type 2 (cardiac)]], [[TNNT2]]
**[[Tropomyosin 1 (alpha)]], [[TPM1]]
**[[Titin]], [[TTN]]
**[[Vinculin]], [[VCL]]
{{col-end}}


====Genes Encoding Calcium Handling Proteins====
====Genes Encoding Calcium Handling Proteins====
**[[Phospholamban]], [[PLN]]
:*[[Phospholamban]], [[PLN]]


====Genes Encoding Mitochondrial Proteins====
====Genes Encoding Mitochondrial Proteins====
**[[Succinate dehydrogenase complex, subunit A, flavoprotein]], [[SDHA]]
:*[[Succinate dehydrogenase complex, subunit A, flavoprotein]], [[SDHA]]


'''*Genes Encoding Nuclear Proteins'''
====Genes Encoding Nuclear Proteins====
**[[ATP-binding cassette, sub-family C, member 9]], [[ABCC9]]
:*[[ATP-binding cassette, sub-family C, member 9]], [[ABCC9]]
**[[Emerin]], EMD
:*[[Emerin]], EMD
**[[Forkhead box D4]], [[FOXD4]]
:*[[Forkhead box D4]], [[FOXD4]]
**[[Lamin A/C]], [[LMNA]]
:*[[Lamin A/C]], [[LMNA]]
**[[Spectrin repeat containing, nuclear envelope 1]], [[SYNE1]]
:*[[Spectrin repeat containing, nuclear envelope 1]], [[SYNE1]]
**[[Spectrin repeat containing, nuclear envelope 2]], [[SYNE2]]
:*[[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 <ref name="pmid23281406">{{cite journal| author=McNally EM, Golbus JR, Puckelwartz MJ| title=Genetic mutations and mechanisms in dilated cardiomyopathy. | journal=J Clin Invest | year= 2013 | volume= 123 | issue= 1 | pages= 19-26 | pmid=23281406 | doi=10.1172/JCI62862 | pmc=PMC3533274 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23281406 }} </ref>. 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. <ref name="pmid22763267">{{cite journal| author=Golbus JR, Puckelwartz MJ, Fahrenbach JP, Dellefave-Castillo LM, Wolfgeher D, McNally EM| title=Population-based variation in cardiomyopathy genes. | journal=Circ Cardiovasc Genet | year= 2012 | volume= 5 | issue= 4 | pages= 391-9 | pmid=22763267 | doi=10.1161/CIRCGENETICS.112.962928 | pmc=PMC3495587 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22763267 }} </ref>
The increase in whole exome and whole genome sequencing has significantly increased the number of rare variants that are associated with dilated cardiomyopathy <ref name="pmid23281406">{{cite journal| author=McNally EM, Golbus JR, Puckelwartz MJ| title=Genetic mutations and mechanisms in dilated cardiomyopathy. | journal=J Clin Invest | year= 2013 | volume= 123 | issue= 1 | pages= 19-26 | pmid=23281406 | doi=10.1172/JCI62862 | pmc=PMC3533274 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23281406 }} </ref>. 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. <ref name="pmid22763267">{{cite journal| author=Golbus JR, Puckelwartz MJ, Fahrenbach JP, Dellefave-Castillo LM, Wolfgeher D, McNally EM| title=Population-based variation in cardiomyopathy genes. | journal=Circ Cardiovasc Genet | year= 2012 | volume= 5 | issue= 4 | pages= 391-9 | pmid=22763267 | doi=10.1161/CIRCGENETICS.112.962928 | pmc=PMC3495587 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22763267 }} </ref>


===Genetic Testing===
===Genetic Testing===
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Revision as of 03:51, 11 October 2013


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-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
BCL2-associated athanogene 3 BAG3
Cardiotropin CTF1
Cysteine and glycine-rich protein 3 CSRP3
Desmin DES
Desmocollin 2 DSC2
Desmoplakin DSP
DNAJ (Hsp40) homology, subfamily C, member 19 DNAJC19
Dystrophin DMD
Eyes absent homology 4 EYA4
Four and a half LIM domains 2 FHL2
Fukutin FKTN
Lysosomal-associated membrane protein 2 LAMP2
LIM domain binding 3 LDB3
Myosin binding protein C, cardiac MYBPC3
Myosin, heavy chain 6, cardiac muscle, alpha MYH6
Myosin, heavy chain 7, cardiac muscle, alpha MYH7
Nexilin (F actin binding protein) NEXN
Presenilin 1 PSEN1
Presenilin 2 PSEN2
RNA binding motif protein 20 RBM20
Sarcoglycan alpha SGCD
Sodium channel, volatage-gated, type V, alpha subunit SCN5A
Tafazzin TAZ
Titin-cap TCAP
Thymopoietin TMPO
Troponin C type 1 (slow) TNNC1
Troponin I type 3 (cardiac) TNNI3
Troponin T type 2 (cardiac) TNNT2
Tropomyosin 1 (alpha) TPM1
Titin TTN
Vinculin VCL

Genes Encoding Calcium Handling Proteins

Genes Encoding Mitochondrial Proteins

Genes Encoding Nuclear Proteins

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. [8]

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

  • Cardiomyopathy: Gross excellent view of mitral valve from left atrium anterior leaflet appears to balloon a bit into the atrium

    Cardiomyopathy: Gross excellent view of mitral valve from left atrium anterior leaflet appears to balloon a bit into the atrium

  • Cardiomyopathy: Gross excellent view of mitral and tricuspid valves from atria, appear normal anatomy.

    Cardiomyopathy: Gross excellent view of mitral and tricuspid valves from atria, appear normal anatomy.

  • Dilated Cardiomyopathy: Gross natural color close-up view of heart surgically removed for a transplantation shows aortic valve and anterior leaflet of mitral valve with cholesterol deposits endocardium of left ventricle is diffusely thickened

    Dilated Cardiomyopathy: Gross natural color close-up view of heart surgically removed for a transplantation shows aortic valve and anterior leaflet of mitral valve with cholesterol deposits endocardium of left ventricle is diffusely thickened

  • Cardiomyopathy: Gross external view of globular heart with patchy fibrosis seen through epicardium

    Cardiomyopathy: Gross external view of globular heart with patchy fibrosis seen through epicardium

  • Cardiomyopathy: Gross dilated left ventricle with marked endocardial thickening this is what has been called adult fibroelastosis

    Cardiomyopathy: Gross dilated left ventricle with marked endocardial thickening this is what has been called adult fibroelastosis

  • Dilated Cardiomyopathy: Gross good example huge dilated left ventricle

    Dilated Cardiomyopathy: Gross good example huge dilated left ventricle

  • Dilated Cardiomyopathy: Gross dilated left ventricle with marked endocardial sclerosis (an excellent example)

    Dilated Cardiomyopathy: Gross dilated left ventricle with marked endocardial sclerosis (an excellent example)

  • Cardiomyopathy: Gross intact globular shaped heart

    Cardiomyopathy: Gross intact globular shaped heart

  • Dilated Cardiomyopathy: Gross opened left ventricle dilated with endocardial thickening good example

    Dilated Cardiomyopathy: Gross opened left ventricle dilated with endocardial thickening good example

  • Cardiomyopathy: Gross globular heart external view 10 year old girl with sickle cell anemia

    Cardiomyopathy: Gross globular heart external view 10 year old girl with sickle cell anemia

  • Cardiomyopathy: Gross horizontal sections of ventricles dilation type 10 year old girl with sickle cell anemia

    Cardiomyopathy: Gross horizontal sections of ventricles dilation type 10 year old girl with sickle cell anemia

  • Cardiomyopathy: Intermediate between hypertrophic and dilated

    Cardiomyopathy: Intermediate between hypertrophic and dilated

  • Dilated Cardiomyopathy: Gross opened globular left ventricle natural color (very good example)

    Dilated Cardiomyopathy: Gross opened globular left ventricle natural color (very good example)

  • Dilated Cardiomyopathy: Gross natural color external view globular heart 500 gm 24yo female seven pregnancies

    Dilated Cardiomyopathy: Gross natural color external view globular heart 500 gm 24yo female seven pregnancies

References

  1. ↑ 1.0 1.1 1.2 1.3 Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D; et al. (2006). "Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention". Circulation. 113 (14): 1807–16. doi:10.1161/CIRCULATIONAHA.106.174287. PMID 16567565.
  2. ↑ 2.0 2.1 McNally EM, Golbus JR, Puckelwartz MJ (2013). "Genetic mutations and mechanisms in dilated cardiomyopathy". J Clin Invest. 123 (1): 19–26. doi:10.1172/JCI62862. PMC 3533274. PMID 23281406.
  3. ↑ Knöll R, Postel R, Wang J, Krätzner R, Hennecke G, Vacaru AM; et al. (2007). "Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells". Circulation. 116 (5): 515–25. doi:10.1161/CIRCULATIONAHA.107.689984. PMID 17646580.
  4. ↑ {{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
  5. ↑ Trabelsi M, Kavian N, Daoud F, Commere V, Deburgrave N, Beugnet C; et al. (2008). "Revised spectrum of mutations in sarcoglycanopathies". Eur J Hum Genet. 16 (7): 793–803. doi:10.1038/ejhg.2008.9. PMID 18285821.
  6. ↑ Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT (1998). "Actin mutations in dilated cardiomyopathy, a heritable form of heart failure". Science. 280 (5364): 750–2. PMID 9563954.
  7. ↑ Mohapatra B, Jimenez S, Lin JH, Bowles KR, Coveler KJ, Marx JG; et al. (2003). "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis". Mol Genet Metab. 80 (1–2): 207–15. PMID 14567970.
  8. ↑ Golbus JR, Puckelwartz MJ, Fahrenbach JP, Dellefave-Castillo LM, Wolfgeher D, McNally EM (2012). "Population-based variation in cardiomyopathy genes". Circ Cardiovasc Genet. 5 (4): 391–9. doi:10.1161/CIRCGENETICS.112.962928. PMC 3495587. PMID 22763267.

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