Dilated cardiomyopathy pathophysiology: Difference between revisions

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


{{CMG}}; {{AE}} Sachin Shah, M.D., Jennifer Hall {{AIA}}
{{CMG}}; {{AE}} Sachin Shah, M.D.; Jennifer Hall; {{AIA}}


==Overview==
==Overview==
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* Initiating the process of [[Congestive heart failure|heart failure]] that causes more myocyte injury.<ref name="pmid28190577">{{cite journal| author=Weintraub RG, Semsarian C, Macdonald P| title=Dilated cardiomyopathy. | journal=Lancet | year= 2017 | volume= 390 | issue= 10092 | pages= 400-414 | pmid=28190577 | doi=10.1016/S0140-6736(16)31713-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28190577  }}</ref>
* Initiating the process of [[Congestive heart failure|heart failure]] that causes more myocyte injury.<ref name="pmid28190577">{{cite journal| author=Weintraub RG, Semsarian C, Macdonald P| title=Dilated cardiomyopathy. | journal=Lancet | year= 2017 | volume= 390 | issue= 10092 | pages= 400-414 | pmid=28190577 | doi=10.1016/S0140-6736(16)31713-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28190577  }}</ref>


===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.


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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>
===Associated Conditions===
==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:
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:
*S[[systemic lupus erythematosis|ystemic lupus erythematosis]]
*S[[systemic lupus erythematosis|ystemic lupus erythematosis]]
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*[[Pericardial effusion]] - It may accompany myocarditis but this finding is not specific.
*[[Pericardial effusion]] - It may accompany myocarditis but this finding is not specific.


===Gross Pathology===
==Gross Pathology==
On gross pathological examination, the heart may show
On gross pathological examination, the heart may show


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</div>
</div>


===Microscopic Pathology===
==Microscopic Pathology==
On microscopic pathological examination, the heart may show
On microscopic pathological examination, the heart may show


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* Myofiber disarray
* Myofiber disarray
* Transmural scars may be present.
* Transmural scars may be present.
* Further, microscopic examination can verify the underlying cause as inflammation, amyloid, iron, and granulomas
* Further, microscopic examination can verify the underlying cause as inflammation, amyloid, iron, and granulomas.<ref name="pmid20189027">{{cite journal| author=Jefferies JL, Towbin JA| title=Dilated cardiomyopathy. | journal=Lancet | year= 2010 | volume= 375 | issue= 9716 | pages= 752-62 | pmid=20189027 | doi=10.1016/S0140-6736(09)62023-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20189027  }}</ref>


==References==
==References==

Latest revision as of 17:41, 7 January 2020

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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; Abdelrahman Ibrahim Abushouk, MD[2]

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. Phenotypic characteristics typically include ventricular chamber enlargement and systolic dysfunction with normal wall thickness. 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. Dilated cardiomyopathy is the third most common cause of heart failure.

Pathophysiology

Physiology

The normal physiology of myocardium can be understood as follows:

  • The myocardium is composed of specialized cardiac muscle cells with an ability not possessed by muscle tissue elsewhere in the body. Cardiac muscle, like other muscles, can contract, but it can also carry an action potential (i.e. conduct electricity), like the neurones that constitute nerves.
  • The cardiac myocyte is a specialized muscle cell, which is composed of bundles of myofibrils that contain myofilaments. The myofibrils have distinct micro-anatomical units, called "sarcomeres", which are considered as the basic contractile units of the cardiac cell. The sarcomere is defined as the region of myofilament structures between two Z-lines. The distance between Z-lines ranges between 1.6 and 2.2 μ. The sarcomere is composed of thick (myosin) and thin (actin) filaments. The chemical and physical interactions between the actin and myosin shortens the sarcomere length and the myocyte to contract during the process of excitation-contraction coupling, which is known as the "sliding filament theory of muscle contraction".[1]
Figure. Sarcomere, pictured with component proteins actin, myosin, titin, etc.

Pathogenesis

Dilated cardiomyopathy usually results from a failed physiological response to myocyte injury. Mocyte injury can generally end in one of three outcomes: Immediate myocyte cell death, delayed myocyte cell death (apoptosis), or pathological compensatory response.[2] The third outcome usually results in a cycle that occurs as follows:

  • Myocyte injury
  • Hypertrophy of the remaining myocytes to increased wall stress
  • Hyperadrenergic response
  • Dynamic remodeling of the interstitial myocardial skeleton (e.g. fibrosis).
  • Reduced diastolic function and increased ventricular dilatation.
  • Distortion of valvular apparatus
  • Increased ventricular afterload
  • Initiating the process of heart failure that causes more myocyte injury.[3]

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.[4] These mutations are listed below.

Genes Encoding Plasma Membrane Proteins

Gene Abbreviation
Laminin alpha 4 LAMA4[5]
Sarcoglycan delta SGCD[6][7]

Genes Encoding Cytoskeletal Proteins

Gene Abbreviation
Actin, alpha, cardiac muscle 1 ACTC1[8]
Actinin, alpha 2 ACTN2[9]
Ankyrin repeat domain 1 ANKRD1[10]
BCL2-associated athanogene 3 BAG3[11]
Cardiotropin CTF1[12]
Cysteine and glycine-rich protein 3 CSRP3[9]
Desmin DES[13] [14]
Desmoplakin DSP[15][16][17]
DNAJ (Hsp40) homology, subfamily C, member 19 DNAJC19[18]
Dystrophin DMD[19][20][21][22][23][24][25]
Eyes absent homology 4 EYA4[26]

[27]

Four and a half LIM domains 2 FHL2[28]
Fukutin FKTN[29]
Lysosomal-associated membrane protein 2 LAMP2[30]
LIM domain binding 3 LDB3[31][32][33][34]
Myosin binding protein C, cardiac MYBPC3[35]
Myosin, heavy chain 6, cardiac muscle, alpha MYH6[36]
Myosin, heavy chain 7, cardiac muscle, alpha MYH7[37]|

[38]

Nexilin (F actin binding protein) NEXN[39]
Presenilin 1 PSEN1[40]
Presenilin 2 PSEN2[40]
RNA binding motif protein 20 RBM20[41][42]
Sarcoglycan alpha SGCD[6][7]
Sodium channel, volatage-gated, type V, alpha subunit SCN5A[34][43][44][45][46][47]
Tafazzin TAZ[48][49]
Thymopoietin TMPO[50]
Troponin C type 1 (slow) TNNC1[51]
Troponin I type 3 (cardiac) TNNI3[52][53]
Troponin T type 2 (cardiac) TNNT2[38][54][51][55][56][57][58]
Tropomyosin 1 (alpha) TPM1[59][60]
Titin TTN[61][62][63]
Vinculin VCL[64][65]

Genes Encoding Calcium Handling Proteins

Gene Abbreviation
Phospholamban PLN[66][67][68][69][70][71][72][73]

Genes Encoding Mitochondrial Proteins

Gene Abbreviation
Succinate dehydrogenase complex, subunit A, flavoprotein SDHA[74]

Genes Encoding Nuclear Proteins

Gene Abbreviation
ATP-binding cassette, sub-family C, member 9 ABCC9[75]
Lamin A/C LMNA[76][77][78][79][80][81][82][83]
Spectrin repeat containing, nuclear envelope 2 SYNE2[84]

The increase in whole exome and whole genome sequencing has significantly increased the number of rare variants that are associated with dilated cardiomyopathy [4]. 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. [85]

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

On gross pathological examination, the heart may show

  • Globular heart (markedly dilated ventricles > 4 cm at the level of papillary muscles)
  • Patchy fibrosis in the epicardium
  • Endocardial thickening (Cardiac fibroelastosis)
  • Ballooning of valve leaflets into the atria
  • Few patients show left ventricular non-compaction or minimally dilated ventricles.

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 view from the left atrium, in which the mitral valve anterior leaflet appears to balloon a bit into the atrium

    Cardiomyopathy: Gross view from the left atrium, in which the mitral valve anterior leaflet appears to balloon a bit into the atrium

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

    Cardiomyopathy: Gross view of mitral and tricuspid valves from the atria, showing normal anatomy.

  • Cardiomyopathy: Gross dilated left ventricle with marked endocardial thickening "adult fibroelastosis"

    Cardiomyopathy: Gross dilated left ventricle with marked endocardial thickening "adult fibroelastosis"

  • Dilated Cardiomyopathy: Gross dilated left ventricle

    Dilated Cardiomyopathy: Gross dilated left ventricle

  • Dilated Cardiomyopathy: Gross dilated left ventricle with marked endocardial sclerosis

    Dilated Cardiomyopathy: Gross dilated left ventricle with marked endocardial sclerosis

  • Cardiomyopathy: Gross intact globular shaped heart

    Cardiomyopathy: Gross intact globular shaped heart

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

    Dilated Cardiomyopathy: Gross opened dilated left ventricle with endocardial thickening

  • Cardiomyopathy: Gross globular heart (external view) in a 10-year old girl with sickle cell anemia

    Cardiomyopathy: Gross globular heart (external view) in a 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

    Dilated Cardiomyopathy: Gross opened globular left ventricle

Microscopic Pathology

On microscopic pathological examination, the heart may show

  • Variations in myocyte size
  • Interstitial fibrosis
  • Myofiber disarray
  • Transmural scars may be present.
  • Further, microscopic examination can verify the underlying cause as inflammation, amyloid, iron, and granulomas.[86]

References

  1. ↑ Janssen PM (2010). "Myocardial contraction-relaxation coupling". Am J Physiol Heart Circ Physiol. 299 (6): H1741–9. doi:10.1152/ajpheart.00759.2010. PMC 3006276. PMID 20852049.
  2. ↑ Schultheiss HP, Fairweather D, Caforio ALP, Escher F, Hershberger RE, Lipshultz SE; et al. (2019). "Dilated cardiomyopathy". Nat Rev Dis Primers. 5 (1): 32. doi:10.1038/s41572-019-0084-1. PMID 31073128.
  3. ↑ Weintraub RG, Semsarian C, Macdonald P (2017). "Dilated cardiomyopathy". Lancet. 390 (10092): 400–414. doi:10.1016/S0140-6736(16)31713-5. PMID 28190577.
  4. ↑ 4.0 4.1 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.
  5. ↑ 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.
  6. ↑ 6.0 6.1 {{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
  7. ↑ 7.0 7.1 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.
  8. ↑ 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.
  9. ↑ 9.0 9.1 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.
  10. ↑ Duboscq-Bidot L, Charron P, Ruppert V, Fauchier L, Richter A, Tavazzi L; et al. (2009). "Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy". Eur Heart J. 30 (17): 2128–36. doi:10.1093/eurheartj/ehp225. PMID 19525294.
  11. ↑ Norton N, Li D, Rieder MJ, Siegfried JD, Rampersaud E, Züchner S; et al. (2011). "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy". Am J Hum Genet. 88 (3): 273–82. doi:10.1016/j.ajhg.2011.01.016. PMC 3059419. PMID 21353195.
  12. ↑ Erdmann J, Hassfeld S, Kallisch H, Fleck E, Regitz-Zagrose V (2000). "Genetic variants in the promoter (g983G>T) and coding region (A92T) of the human cardiotrophin-1 gene (CTF1) in patients with dilated cardiomyopathy". Hum Mutat. 16 (5): 448. doi:10.1002/1098-1004(200011)16:5<448::AID-HUMU19>3.0.CO;2-D. PMID 11058912.
  13. ↑ Li D, Tapscoft T, Gonzalez O, Burch PE, Quiñones MA, Zoghbi WA; et al. (1999). "Desmin mutation responsible for idiopathic dilated cardiomyopathy". Circulation. 100 (5): 461–4. PMID 10430757.
  14. ↑ Bergman JE, Veenstra-Knol HE, van Essen AJ, van Ravenswaaij CM, den Dunnen WF, van den Wijngaard A; et al. (2007). "Two related Dutch families with a clinically variable presentation of cardioskeletal myopathy caused by a novel S13F mutation in the desmin gene". Eur J Med Genet. 50 (5): 355–66. doi:10.1016/j.ejmg.2007.06.003. PMID 17720647.
  15. ↑ Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE; et al. (2000). "Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma". Hum Mol Genet. 9 (18): 2761–6. PMID 11063735.
  16. ↑ Uzumcu A, Norgett EE, Dindar A, Uyguner O, Nisli K, Kayserili H; et al. (2006). "Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome". J Med Genet. 43 (2): e5. doi:10.1136/jmg.2005.032904. PMC 2564645. PMID 16467215.
  17. ↑ Rasmussen TB, Hansen J, Nissen PH, Palmfeldt J, Dalager S, Jensen UB; et al. (2013). "Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms". Clin Genet. 84 (1): 20–30. doi:10.1111/cge.12056. PMID 23137101.
  18. ↑ Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P; et al. (2006). "Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition". J Med Genet. 43 (5): 385–93. doi:10.1136/jmg.2005.036657. PMC 2564511. PMID 16055927.
  19. ↑ Ferlini A, Galié N, Merlini L, Sewry C, Branzi A, Muntoni F (1998). "A novel Alu-like element rearranged in the dystrophin gene causes a splicing mutation in a family with X-linked dilated cardiomyopathy". Am J Hum Genet. 63 (2): 436–46. doi:10.1086/301952. PMC 1377294. PMID 9683584.
  20. ↑ Ortiz-Lopez R, Li H, Su J, Goytia V, Towbin JA (1997). "Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy". Circulation. 95 (10): 2434–40. PMID 9170407.
  21. ↑ Todorova A, Constantinova D, Kremensky I (2003). "Dilated cardiomyopathy and new 16 bp deletion in exon 44 of the Dystrophin gene: the possible role of repeated motifs in mutation generation". Am J Med Genet A. 120A (1): 5–7. doi:10.1002/ajmg.a.10264. PMID 12794683.
  22. ↑ Milasin J, Muntoni F, Severini GM, Bartoloni L, Vatta M, Krajinovic M; et al. (1996). "A point mutation in the 5' splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy". Hum Mol Genet. 5 (1): 73–9. PMID 8789442.
  23. ↑ Muntoni F, Cau M, Ganau A, Congiu R, Arvedi G, Mateddu A; et al. (1993). "Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy". N Engl J Med. 329 (13): 921–5. doi:10.1056/NEJM199309233291304. PMID 8361506.
  24. ↑ Towbin JA, Ortiz-Lopez R (1994). "X-linked dilated cardiomyopathy". N Engl J Med. 330 (5): 369–70. PMID 8123157.
  25. ↑ Muntoni F, Melis MA, Ganau A, Dubowitz V (1995). "Transcription of the dystrophin gene in normal tissues and in skeletal muscle of a family with X-linked dilated cardiomyopathy". Am J Hum Genet. 56 (1): 151–7. PMC 1801315. PMID 7825571.
  26. ↑ Schönberger J, Levy H, Grünig E, Sangwatanaroj S, Fatkin D, MacRae C; et al. (2000). "Dilated cardiomyopathy and sensorineural hearing loss: a heritable syndrome that maps to 6q23-24". Circulation. 101 (15): 1812–8. PMID 10769282.
  27. ↑ Schönberger J, Wang L, Shin JT, Kim SD, Depreux FF, Zhu H; et al. (2005). "Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss". Nat Genet. 37 (4): 418–22. doi:10.1038/ng1527. PMID 15735644.
  28. ↑ Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T; et al. (2007). "Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy". Biochem Biophys Res Commun. 357 (1): 162–7. doi:10.1016/j.bbrc.2007.03.128. PMID 17416352.
  29. ↑ Murakami T, Hayashi YK, Noguchi S, Ogawa M, Nonaka I, Tanabe Y; et al. (2006). "Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness". Ann Neurol. 60 (5): 597–602. doi:10.1002/ana.20973. PMID 17036286.
  30. ↑ Taylor MR, Ku L, Slavov D, Cavanaugh J, Boucek M, Zhu X; et al. (2007). "Danon disease presenting with dilated cardiomyopathy and a complex phenotype". J Hum Genet. 52 (10): 830–5. doi:10.1007/s10038-007-0184-8. PMID 17899313.
  31. ↑ Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z; et al. (2003). "Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction". J Am Coll Cardiol. 42 (11): 2014–27. PMID 14662268.
  32. ↑ Arimura T, Inagaki N, Hayashi T, Shichi D, Sato A, Hinohara K; et al. (2009). "Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy". Cardiovasc Res. 83 (1): 80–8. doi:10.1093/cvr/cvp119. PMID 19377068.
  33. ↑ Arimura T, Hayashi T, Terada H, Lee SY, Zhou Q, Takahashi M; et al. (2004). "A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C." J Biol Chem. 279 (8): 6746–52. doi:10.1074/jbc.M311849200. PMID 14660611.
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