Dilated Cardiomyopathy – Exploring the Underlying Causes
Main Article Content
Abstract
Cardiovascular disease is one of the world’s leading causes of natural mortality, taking approximately 18 million lives each year. Dilated cardiomyopathy, a subgroup of cardiac diseases, has an annual incidence of 5 – 8 cases per 100,000 for European and North American populations. Common features of dilated cardiomyopathy include cardiac chamber enlargement, impaired systolic function, reduced ejection fraction, and arrhythmias, with an endpoint of ventricular dilation and heart failure. The focus of this paper is to review the non-genetic and genetic etiologies that lead to dilated cardiomyopathy. The non-genetic causes of dilated cardiomyopathy that are discussed include viruses, cardiotoxicity, recreational drugs, and chemotherapeutic medications. For the genes that lead to dilated cardiomyopathy, the focus of this paper is on cytoskeletal and sarcomeric protein genes. Our scope in defining this area will be to explore numerous mouse models that incorporate mutations found in humans that lead to dilated cardiomyopathy. The purpose of the paper is to define the morphological and physiological consequences of these mutations and how this information has furthered our understanding of the disease. Having gained invaluable knowledge from these animal models, it is hoped that new and improved therapeutic approaches can be developed for the treatment and prevention of dilated cardiomyopathy.
Keywords:
Dilated cardiomyopathy, Heart failure, Cardiac hypertrophy, Cardiac remodeling, Genetic mutations, Cytoskeletal proteins, Sarcomeric proteins, Viral myocarditis, Cardiotoxicity, Mouse models
Article Details
How to Cite
WIECZOREK, David F..
Dilated Cardiomyopathy – Exploring the Underlying Causes.
Medical Research Archives, [S.l.], v. 12, n. 12, dec. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6111>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.6111.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. Harding D, Chong MH, Lahoti N, et al. Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy. J intern Med 2023; 293:23-47.
3. Heymans S, Lakdawala NK, Tshope C, Klingel K. Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches. Lancet 2023; 402:998-1011.
4. Cowie MR. The heart failure epidemic: a UK perspective. Echo Res Pract. 2017;4:R15-20.
5. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006;296:1867-1876.
6. McNamara DM, Starling RC, Cooper LT, et al. Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J Am Cell Cardiol. 2011;58:1112-1118.
7. Castelli F, Fornaro A, Ciaccheri M, et al. Improving survival rates of patients with idiopathic dilated cardiomyopathy in Tuscany over 3 decades: impact of evidence-based management. Circ Heart Fail. 2013;6:913-921.
8. Blyszczuk P. Myocarditis in humans and in experimental animal models. Front Cardiovasc Med. 2019;6:64-81,
9. Matsumori A, Kawai C. An animal model of congestive (dilated) cardiomyopathy: dilatation and hypertrophy of the heart in the chronic stage in DBA/2 mice with myocarditis caused by encephalomyocarditis virus. Circulation. 1982;66: 355-360.
10. Dec GW, Palacios IF, Fallon JT, et al. Active myocarditis in the spectrum of acute dilated cardiomyopathies. N Engl J Med. 1985;312:885-890.
11. D’Ambrosio A, Patti G, Manzoli A, et al. The fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: a review. Heart. 2001;85:499-504.
12. Caforio AL, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. European Heart Journal 2013;34:2636-2648.
13. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial investigators. N Engl J Med. 1995;333:269-275.
14. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure. Circulation. 2004;109:1594-1602.
15. Caforio AL, Adler Y, Agostini C. et al. Diagnosis and management of myocardial involvement in systemic immune-mediated diseases: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur Heart J 2017;38:2649-2662.
16. Fauchier L, Babuty D, Poret P, et al. Comparison of long-term outcome of alcoholic and idiopathic dilated cardiomyopathy. European Heart J 2000;21:306-314.
17. Figueredo VM. Chemical cardiomyopathies: the negative effects of medications and nonprescribed drugs on the heart. Amer J Med 2011;124:480-488.
18. Weintraub R, Semsarian C, Macdonald P. Dilated cardiomyopathy. Lancet 2017; 390:400-414.
19. Wieczorek DF. Cardiomyopathy: getting bigger all of the time – lessons learned about heart disease from tropomyosin. In Cardiomyopathy – Disease of the Heart Muscle (ed. G. Mattsson and P. Magnusson) IntechOpen, London, UK, 2021; pp287-303.
20. Hershberger R, Hedges D, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev. Cardiol. 2013;10:531-547.
21. Wieczorek DF. Sarcomeric thin filament associated cardiomyopathic mouse models. Medical Research Archives 2023;11(9). https://doi.org/a0.18103/mra.v11i9.4369.
22. McNally EM…Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest. 2013;123:19-26.
23. McNally EM, Mestroni L. Dilated cardiomyopathy – genetic determinants and mechanisms. Circ Res 2017;121:731-748.
24. Rajan S, Ahmed R, Jagatheesan G, et al. Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity. Circ Res 2007;101:205-214.
25. Manolio TA, Baughman KL, Rodeheffer R, et al. Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute workshop). Am J Cardiol 1992;69:1458-1466.
26. van der Zwaag, van Rijsingen I, Asimaki A, et al. Phospholamban r14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012;14:1199-1207.
27. Ikeda Y, Ross J.Jr. Models of dilated cardiomyopathy in the mouse and the hamster. Current Opinion in Cardiology 2000; 15:197-201.
28. Recchia FA, Lionetti V. Animal models in dilated cardiomyopathy for translational research. Vet Res Comm. 2007;31:35-41.
29. Yoo KJ, Li RK, Weisel RD, et al. Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters. Circ. 2000;102:204-209.
30. Nikolova V, Leimena C, McMahon A, et al. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 2004;113:357-369.
31. Wolf CM, Wang L, Alcalai R. et al. Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease. J Mol. Cell. Cardiol. 2008;44:293-303.
32. Chandar S, Yeo LS, Leimena C, et al. Effects of mechanical stress and carvedilol in lamin A/C-deficient dilated cardiomyopathy. Circ Res 2010; 106:573-582.
33. Ramos FJ, Chen SC, Garelick MG, et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med. 2013;4(144):144ra103.
34. Choi JC, Muchir A, Wu W, et al, Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. Sci Transl Med 2012;4(144)ra102.
35. Fatkin D, Huttner IG. Titin-truncating mutations in dilated cardiomyopathy: the long and short of it. Curr Opin Cardiol 2017;32:232-238.
36. Gramlich M, Michely B, Krohne C. et al. Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease. J Mol Cell Cardiol 2009;47:352-358.
37. Yu D, Tao L, Song L, et al. Integrated multi-omics approach revealed TTNtv c.13254T>G causing dilated cardiomyopathy in mice. PLoS ONE 2024;19:e0311670.
38. Zhou Q, Kesteven S, Wu J, et al. Pressure overload by transverse aortic constriction induces maladaptive hypertrophy in a titin-truncated mouse model. BioMed Research International 2015: Article ID 163564.
39. Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nature Genetics 2002;30:201-204.
40. Gramlich M, Pane LS, Zhou Q, et al. Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy. EMBO Molecular Medicine 2015;7:562-576.
41. Lanfear DE, Reza N. Moysin-related dilated cardiomyopathy – another elephant emerges from darkness. J. Amer Coll Cardiology 2022;80:1462-1465.
42. de Frutos F, Ochoa JP, Navarro-Penalver M, et al. Natural history of MYH7-related dilated cardiomyopathy. J Amer. Coll Cardiology 2022; 80:1447-1461.
43. Schmitt JP, Debold EP, Ahmad F, et al. Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function. PNAS 2006;103:4525-14530.
44. Trujillo AS, Hsu KH, Puthawala J, et al. Mosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila. Mol Biol Cell 2021;32:1690-1706.
45. McConnell BK, Jones KA, Fatkin D, et al. Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice. J Clin Inves 1999; 104:1235-1244.
46. Lynch TL, Ismahil MA, Jegga A, et al. Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation. J Mol Cell Cardiol. 2017;102:83-93.
47. Lu M, DiLullo C, Schultheiss T, et al. The vinculin/sarcomeric-alpha-actinin/alpha-actin nexus in cultured cardiac myocytes. J Cell Biol 1992; 117:1107-1022.
48. Gregoria C. Models of thin filament assembly in cardiac and skeletal muscle. Cell Struct Funct. 1997; 22:191-195.
49. Kumar A, Crawford K, Close L, et al. Rescue of cardiac a-actin-deficient mice by enteric smooth muscle g-actin. Proc Natl. Acad. Sci USA 1997; 94:4406-4411.
50. Rajan S, Jagatheesan G, Karam C, et al. Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform. Circ 2010; 121:410-418.
51. Muthuchamy S, Pajak L, Howles P, et al. Developmental analysis of tropomyosin gene expression in embryonic stem cells and mouse embryos. Mol Cell Biol 1993; 13:3311-3323.
52. Warren CM, Arteaga GM, Rajan S, et al. Use of 2-D DIGE analysis reveals altered phosphorylation in a tropomyosin mutant (GLU54LYS) linked to dilated cardiomyopathy. Proteomics 2008;8:100-105.
53. Wieczorek DF. Implications of tropomyosin phosphorylation in normal and cardiomyopathic hearts. Med. Res. Arch. 2022; 10(8). https://doi.org/10.18193/mra. V10i8.3103 .
54. Rajan S, Jagatheesan G, Petrashevskaya N, et al. Tropomyosin pseudo-phosphorylation results in dilated cardiomyopathy. J Biol Chem 2019; 294 :2913-2923.
55. Matyushenko AM, Koubassova NA, Shchepkin D, et al. The effects of cardiomyopathy-associated mutations in the head-to-tail overlap junction of a-tropomyosin on its properties and interaction with actin. International Journal Biological Macromolecules 2019;125:1266-1274.
56.Kopylova GV, Matyushenko AM, Koubassova NA, et al. Functional outcomes of structural peculiarities of striated muscle tropomyosin. J Mus Res. Cell Motil 2020;41:55-70.
57. McConnell M, Grinspan LT, Williams MR, et al. Clinically divergent mutation effects on the structure and function of the human cardiac tropomyosin overlap. Biochemistry 2018; 56:3403-3413.
58. Lehrer SS, Geeves MA. The myosin-activated thin filament regulatory state, M- open: a link to hypertrophic cardiomyopathy (HCM). J. Muscle Res. Cell Motil 2014;35:153-160.
59. Muthuchamy M, Grupp I, Grupp G et al. Molecular and physiological effects of overexpressing striated muscle beta-tropomyosin in the adult murine heart. J Biol Chem 1995; 270:30593-30603.
60. Muthuchamy M, Boivin G, Grupp I, Wieczorek DF. β-tropomyosin overexpression induces severe cardiac abnormalities. J Mol Cell Cardiol 1998; 30:1545-1557.
61. Sussman M, Lim H, Gude N, et al. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 1998; 281:1690-1693.
62. Lu Q-W, Wu Z-Y, Morimoto S. Inherited cardiomyopathies caused by troponin mutations. J Geriatric Cardiol 2014; 10:91-101.
63. Kamisago M, Sharma S, DePalma S, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000; 343: 1688-1696.
64. Du C-K, Morimoto S, Nishii K, et al. Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation. Circ Res 2007;101:185-194.
65. Mirza M, Marston S, Willott R, et al., Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. J Biol Chem. 2005;280:28498-28506.
66. Tardiff JC. Thin filament mutations – developing an integrative approach to a complex disorder. Circ Res 2011;108:765-782.
67. Murakami C, Nakamura S, Kobayashi M, et al. Analysis of the sarcomere protein gene mutation on cardiomyopathy – mutations in the cardiac troponin I gene. Legal Med 2010; 112:280-283.
68. Kalyva A, Parthenakis F, Marketou M, et al. Biochemical characterization of troponin C mutations causing hypertrophic and dilated cardiomyopathies. J Muscle Res Cell Motil 2014; 35:161-178.
69. Tobacman L, Cammarato A. Cardiomyopathic troponin mutations predominantly occur at its interface with actin and tropomyosin. J Gen Physiol 2021; 153:1-11.
70. Davis J, Davis L, Correll R. et al. A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 2016; 165:1147-1159.
71. Tanaka Y, Rahmutula D, Duggirala S, et al., Diffuse fibrosis leads to a decrease in unipolar voltage: validation in a swine model of premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 2016;13:547-554.
72. Walters TE, Rahmutula D, Szilagyi J, et al., Left ventricular dyssynchrony predicts the cardiomyopathy associated with premature ventricular contractions. J Amer Coll of Cardiology 2018;72:2870-2882.
73. Torrado J, Kowlgi GN, Ramirez RJ, et al. Eccentric hypertrophy in an animal model of mid-and long-term premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 2021;2:80-88.
74. Balderas-Villalobos J, Medina-Contreras JM, Lynch C, et al. Mechanisms of adaptive hypertrophic cardiac remodeling in a large animal model of premature ventricular contraction-induced cardiomyopathy. IUBMB Life 2023;75:926-940.
2. Harding D, Chong MH, Lahoti N, et al. Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy. J intern Med 2023; 293:23-47.
3. Heymans S, Lakdawala NK, Tshope C, Klingel K. Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches. Lancet 2023; 402:998-1011.
4. Cowie MR. The heart failure epidemic: a UK perspective. Echo Res Pract. 2017;4:R15-20.
5. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006;296:1867-1876.
6. McNamara DM, Starling RC, Cooper LT, et al. Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J Am Cell Cardiol. 2011;58:1112-1118.
7. Castelli F, Fornaro A, Ciaccheri M, et al. Improving survival rates of patients with idiopathic dilated cardiomyopathy in Tuscany over 3 decades: impact of evidence-based management. Circ Heart Fail. 2013;6:913-921.
8. Blyszczuk P. Myocarditis in humans and in experimental animal models. Front Cardiovasc Med. 2019;6:64-81,
9. Matsumori A, Kawai C. An animal model of congestive (dilated) cardiomyopathy: dilatation and hypertrophy of the heart in the chronic stage in DBA/2 mice with myocarditis caused by encephalomyocarditis virus. Circulation. 1982;66: 355-360.
10. Dec GW, Palacios IF, Fallon JT, et al. Active myocarditis in the spectrum of acute dilated cardiomyopathies. N Engl J Med. 1985;312:885-890.
11. D’Ambrosio A, Patti G, Manzoli A, et al. The fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: a review. Heart. 2001;85:499-504.
12. Caforio AL, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. European Heart Journal 2013;34:2636-2648.
13. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial investigators. N Engl J Med. 1995;333:269-275.
14. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure. Circulation. 2004;109:1594-1602.
15. Caforio AL, Adler Y, Agostini C. et al. Diagnosis and management of myocardial involvement in systemic immune-mediated diseases: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur Heart J 2017;38:2649-2662.
16. Fauchier L, Babuty D, Poret P, et al. Comparison of long-term outcome of alcoholic and idiopathic dilated cardiomyopathy. European Heart J 2000;21:306-314.
17. Figueredo VM. Chemical cardiomyopathies: the negative effects of medications and nonprescribed drugs on the heart. Amer J Med 2011;124:480-488.
18. Weintraub R, Semsarian C, Macdonald P. Dilated cardiomyopathy. Lancet 2017; 390:400-414.
19. Wieczorek DF. Cardiomyopathy: getting bigger all of the time – lessons learned about heart disease from tropomyosin. In Cardiomyopathy – Disease of the Heart Muscle (ed. G. Mattsson and P. Magnusson) IntechOpen, London, UK, 2021; pp287-303.
20. Hershberger R, Hedges D, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev. Cardiol. 2013;10:531-547.
21. Wieczorek DF. Sarcomeric thin filament associated cardiomyopathic mouse models. Medical Research Archives 2023;11(9). https://doi.org/a0.18103/mra.v11i9.4369.
22. McNally EM…Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest. 2013;123:19-26.
23. McNally EM, Mestroni L. Dilated cardiomyopathy – genetic determinants and mechanisms. Circ Res 2017;121:731-748.
24. Rajan S, Ahmed R, Jagatheesan G, et al. Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity. Circ Res 2007;101:205-214.
25. Manolio TA, Baughman KL, Rodeheffer R, et al. Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute workshop). Am J Cardiol 1992;69:1458-1466.
26. van der Zwaag, van Rijsingen I, Asimaki A, et al. Phospholamban r14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012;14:1199-1207.
27. Ikeda Y, Ross J.Jr. Models of dilated cardiomyopathy in the mouse and the hamster. Current Opinion in Cardiology 2000; 15:197-201.
28. Recchia FA, Lionetti V. Animal models in dilated cardiomyopathy for translational research. Vet Res Comm. 2007;31:35-41.
29. Yoo KJ, Li RK, Weisel RD, et al. Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters. Circ. 2000;102:204-209.
30. Nikolova V, Leimena C, McMahon A, et al. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 2004;113:357-369.
31. Wolf CM, Wang L, Alcalai R. et al. Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease. J Mol. Cell. Cardiol. 2008;44:293-303.
32. Chandar S, Yeo LS, Leimena C, et al. Effects of mechanical stress and carvedilol in lamin A/C-deficient dilated cardiomyopathy. Circ Res 2010; 106:573-582.
33. Ramos FJ, Chen SC, Garelick MG, et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med. 2013;4(144):144ra103.
34. Choi JC, Muchir A, Wu W, et al, Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. Sci Transl Med 2012;4(144)ra102.
35. Fatkin D, Huttner IG. Titin-truncating mutations in dilated cardiomyopathy: the long and short of it. Curr Opin Cardiol 2017;32:232-238.
36. Gramlich M, Michely B, Krohne C. et al. Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease. J Mol Cell Cardiol 2009;47:352-358.
37. Yu D, Tao L, Song L, et al. Integrated multi-omics approach revealed TTNtv c.13254T>G causing dilated cardiomyopathy in mice. PLoS ONE 2024;19:e0311670.
38. Zhou Q, Kesteven S, Wu J, et al. Pressure overload by transverse aortic constriction induces maladaptive hypertrophy in a titin-truncated mouse model. BioMed Research International 2015: Article ID 163564.
39. Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nature Genetics 2002;30:201-204.
40. Gramlich M, Pane LS, Zhou Q, et al. Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy. EMBO Molecular Medicine 2015;7:562-576.
41. Lanfear DE, Reza N. Moysin-related dilated cardiomyopathy – another elephant emerges from darkness. J. Amer Coll Cardiology 2022;80:1462-1465.
42. de Frutos F, Ochoa JP, Navarro-Penalver M, et al. Natural history of MYH7-related dilated cardiomyopathy. J Amer. Coll Cardiology 2022; 80:1447-1461.
43. Schmitt JP, Debold EP, Ahmad F, et al. Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function. PNAS 2006;103:4525-14530.
44. Trujillo AS, Hsu KH, Puthawala J, et al. Mosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila. Mol Biol Cell 2021;32:1690-1706.
45. McConnell BK, Jones KA, Fatkin D, et al. Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice. J Clin Inves 1999; 104:1235-1244.
46. Lynch TL, Ismahil MA, Jegga A, et al. Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation. J Mol Cell Cardiol. 2017;102:83-93.
47. Lu M, DiLullo C, Schultheiss T, et al. The vinculin/sarcomeric-alpha-actinin/alpha-actin nexus in cultured cardiac myocytes. J Cell Biol 1992; 117:1107-1022.
48. Gregoria C. Models of thin filament assembly in cardiac and skeletal muscle. Cell Struct Funct. 1997; 22:191-195.
49. Kumar A, Crawford K, Close L, et al. Rescue of cardiac a-actin-deficient mice by enteric smooth muscle g-actin. Proc Natl. Acad. Sci USA 1997; 94:4406-4411.
50. Rajan S, Jagatheesan G, Karam C, et al. Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform. Circ 2010; 121:410-418.
51. Muthuchamy S, Pajak L, Howles P, et al. Developmental analysis of tropomyosin gene expression in embryonic stem cells and mouse embryos. Mol Cell Biol 1993; 13:3311-3323.
52. Warren CM, Arteaga GM, Rajan S, et al. Use of 2-D DIGE analysis reveals altered phosphorylation in a tropomyosin mutant (GLU54LYS) linked to dilated cardiomyopathy. Proteomics 2008;8:100-105.
53. Wieczorek DF. Implications of tropomyosin phosphorylation in normal and cardiomyopathic hearts. Med. Res. Arch. 2022; 10(8). https://doi.org/10.18193/mra. V10i8.3103 .
54. Rajan S, Jagatheesan G, Petrashevskaya N, et al. Tropomyosin pseudo-phosphorylation results in dilated cardiomyopathy. J Biol Chem 2019; 294 :2913-2923.
55. Matyushenko AM, Koubassova NA, Shchepkin D, et al. The effects of cardiomyopathy-associated mutations in the head-to-tail overlap junction of a-tropomyosin on its properties and interaction with actin. International Journal Biological Macromolecules 2019;125:1266-1274.
56.Kopylova GV, Matyushenko AM, Koubassova NA, et al. Functional outcomes of structural peculiarities of striated muscle tropomyosin. J Mus Res. Cell Motil 2020;41:55-70.
57. McConnell M, Grinspan LT, Williams MR, et al. Clinically divergent mutation effects on the structure and function of the human cardiac tropomyosin overlap. Biochemistry 2018; 56:3403-3413.
58. Lehrer SS, Geeves MA. The myosin-activated thin filament regulatory state, M- open: a link to hypertrophic cardiomyopathy (HCM). J. Muscle Res. Cell Motil 2014;35:153-160.
59. Muthuchamy M, Grupp I, Grupp G et al. Molecular and physiological effects of overexpressing striated muscle beta-tropomyosin in the adult murine heart. J Biol Chem 1995; 270:30593-30603.
60. Muthuchamy M, Boivin G, Grupp I, Wieczorek DF. β-tropomyosin overexpression induces severe cardiac abnormalities. J Mol Cell Cardiol 1998; 30:1545-1557.
61. Sussman M, Lim H, Gude N, et al. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 1998; 281:1690-1693.
62. Lu Q-W, Wu Z-Y, Morimoto S. Inherited cardiomyopathies caused by troponin mutations. J Geriatric Cardiol 2014; 10:91-101.
63. Kamisago M, Sharma S, DePalma S, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000; 343: 1688-1696.
64. Du C-K, Morimoto S, Nishii K, et al. Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation. Circ Res 2007;101:185-194.
65. Mirza M, Marston S, Willott R, et al., Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. J Biol Chem. 2005;280:28498-28506.
66. Tardiff JC. Thin filament mutations – developing an integrative approach to a complex disorder. Circ Res 2011;108:765-782.
67. Murakami C, Nakamura S, Kobayashi M, et al. Analysis of the sarcomere protein gene mutation on cardiomyopathy – mutations in the cardiac troponin I gene. Legal Med 2010; 112:280-283.
68. Kalyva A, Parthenakis F, Marketou M, et al. Biochemical characterization of troponin C mutations causing hypertrophic and dilated cardiomyopathies. J Muscle Res Cell Motil 2014; 35:161-178.
69. Tobacman L, Cammarato A. Cardiomyopathic troponin mutations predominantly occur at its interface with actin and tropomyosin. J Gen Physiol 2021; 153:1-11.
70. Davis J, Davis L, Correll R. et al. A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 2016; 165:1147-1159.
71. Tanaka Y, Rahmutula D, Duggirala S, et al., Diffuse fibrosis leads to a decrease in unipolar voltage: validation in a swine model of premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 2016;13:547-554.
72. Walters TE, Rahmutula D, Szilagyi J, et al., Left ventricular dyssynchrony predicts the cardiomyopathy associated with premature ventricular contractions. J Amer Coll of Cardiology 2018;72:2870-2882.
73. Torrado J, Kowlgi GN, Ramirez RJ, et al. Eccentric hypertrophy in an animal model of mid-and long-term premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 2021;2:80-88.
74. Balderas-Villalobos J, Medina-Contreras JM, Lynch C, et al. Mechanisms of adaptive hypertrophic cardiac remodeling in a large animal model of premature ventricular contraction-induced cardiomyopathy. IUBMB Life 2023;75:926-940.