DOI: 10.3724/SP.J.1005.2011.00549

Hereditas (Beijing) (遗传) 2011/33:6 PP.549-557

Advances in the molecular pathogenesis of hypertrophic cardiomyopathy

Hypertrophic Cardiomyopathy (HCM) is a primary cardiac disorder characterized by asymmetric thickening of the septum and left ventricular wall. HCM affects 1 in 500 individuals in the general population, and it is the most common cause of sudden death in the young and athletes. The clinic phenotype of HCM is highly variable with respect to age at onset, degree of symptoms, and risk of sudden death. HCM is usually inherited as a Mendelian autosomal dominant trait. To date, over 900 mutations have been reported in HCM, which were mainly located in 13 genes encoding cardiac sarcomere protein, e.g., MYH7, MYBPC3, and TnT. In addition, more and more mitochondrial DNA mutations were reported to be associated with the pathogenesis of HCM. Based on the description of the clinical phenotype and morphological character-istics, this review focuses on the research in the molecular pathogenic mechanism of HCM and its recent advances.

Key words:hypertrophic cardiomyopathy,genetics,mutations,nuclear genes,mitochondrial DNA

ReleaseDate:2014-07-21 15:52:03

[1] Brock R. Functional obstruction of the left ventricle (acquired aortic subvalvular stenosis). Guys Hosp Rep, 1957, 106(4): 221-238.

[2] Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J, 1958, 20(1): 1-8.

[3] Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes: Clinical, demographic, and pathological profiles. JAMA, 1996, 276(3): 199-204.

[4] Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Trans-plantation Committee; Quality of Care and Outcomes Re-search and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemi-ology and Prevention. Circulation, 2006, 113(14): 1807-1816.

[5] Hershberger RE, Cowan J, Morales A, Siegfried JD. Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Heart Fail, 2009, 2(3): 253-261.

[6] Geisterfer-Lowrance AAT, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a β cardiac myosin heavy chain gene missense mutation. Cell, 1990, 62(5): 999-1006.

[7] Alcalai R, Seidman JG, Seidman CE. Genetic basis of hyper-trophic cardiomyopathy: from bench to the clinics. J Cardiovasc Electr, 2008, 19(1): 104-110.

[8] Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation, 2003, 107(17): 2227-2232.

[9] Soor GS, Luk A, Ahn E, Abraham JR, Woo A, Ralph-Edwards A, Butany J. Hypertrophic cardiomyopathy: current understanding and treatment objectives. J Clin Pathol, 2009, 62(3): 226-235.

[10] Zeviani M, Gellera C, Antozzi C, Rimoldi M, Morandi L, Villani F, Tiranti V, DiDonato S. Maternally inherited myopathy and cardiomyopathy: association with mutation in mitochondrial DNA tRNALeu(UUR). Lancet, 1991, 338(8760): 143-147.

[11] Raha S, Merante F, Shoubridge E, Myint AT, Tein I, Benson L, Johns T, Robinson BH. Repopulation of rho0 cells with mitochondria from a patient with a mitochondrial DNA point mutation in tRNA(Gly) results in respiratory chain dysfunc-tion. Hum Mutat, 1999, 13(3): 245-254.

[12] Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA, 2002, 287(10): 1308-1320.

[13] Bashyam MD, Savithri GR, Kumar MS, Narasimhan C, Nallari P. Molecular genetics of familial hypertrophic cardio-myopathy (FHC). J Hum Genet, 2003, 48(2): 55-64.

[14] Poliac LC, Barron ME, Maron BJ. Hypertrophic cardio-myopathy. Anesthesiology, 2006, 104(1): 183-192.

[15] Tam SK, Gu W, Mahdavi V, Nadal-Ginard B. Cardiac myo-cyte terminal differentiation. Potential for cardiac regeneration. Ann N Y Acad Sci, 1995, 752: 72-79.

[16] Marian AJ. Contemporary treatment of hypertrophic cardio-myopathy. Tex Heart Inst J, 2009, 36(3): 194-204.

[17] Marian AJ. Hypertrophic cardiomyopathy: from genetics to treatment. Eur J Clin Invest, 2010, 40(4): 360-369.

[18] 齐建光, 杜军保. 线粒体心肌病临床诊断和基因研究进展. 中国实用儿科杂志, 2005, 20(6): 374-376.

[19] Marian AJ, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol, 2001, 33(4): 655-670.

[20] Marian AJ. Genetic determinants of cardiac hypertrophy. Curr Opin Cardiol, 2008, 23(3): 199-205.

[21] 李文, 马沛然, 汪翼, 韩秀珍, 丘厚兴. 线粒体DNA点突变与心肌病关系的研究. 山东医药, 1998, 38(7): 3-4.

[22] Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med, 2008, 358(18): 1899-1908.

[23] Seidman CE, Seidman JG. Molecular genetic studies of fa-milial hypertrophic cardiomyopathy. Basic Res Cardiol, 1998, 93(Suppl. 3): 13-16.

[24] Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med, 1998, 338(18): 1248-1257.

[25] Varnava AM, Elliott PM, Baboonian C, Davison F, Davies MJ, McKenna WJ. Hypertrophic cardiomyopathy: histopa-thological features of sudden death in cardiac troponin T dis-ease. Circulation, 2001, 104(12): 1380-1384.

[26] Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang TH, Choo JA, Chung KS, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki M, Sakamoto T, Toshima H, Koga Y, Imaizumi T, Sasazuki T. Mutations in the cardiac troponin I gene associated with hypertrophic cardio-myopathy. Nat Genet, 1997, 16(4): 379-382.

[27] Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. α-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell, 1994, 77(5): 701-712.

[28] Mogensen J, Klausen IC, Pedersen AK, Egeblad H, Bross P, Kruse TA, Gregersen N, Hansen PS, Baandrup U, Børglum AD. α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest, 1999, 103(10): R39-R43.

[29] Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun, 1999, 262(2): 411-417.

[30] Geier C, Perrot A, Özcelik C, Binner P, Counsell D, Hoffmann K, Pilz B, Martiniak Y, Gehmlich K, van der Ven PFM, Fürst DO, Vornwald A, von Hodenberg E, Nürnberg P, Scheffold T, Dietz R, Osterziel KJ. Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy. Circulation, 2003, 107(10): 1390-1395.

[31] Hayashi T, Arimura T, ItohSatoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knöll R, Hoshijima M, Chien KR, Kimura A. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol, 2004, 44(11): 2192-2201.

[32] Osio A, Tan LL, Chen SN, Lombardi R, Nagueh SF, Shete S, Roberts R, Willerson JT, Marian AJ. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ Res, 2007, 100(6): 766-768.

[33] Vasile VC, Ommen SR, Edwards WD, Ackerman MJ. A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy. Biochem Biophys Res Commun, 2006, 345(3): 998-1003.

[34] Tanjore R, RangaRaju A, Vadapalli S, Remersu S, Narsimhan C, Nallari P. Genetic variations of β-MYH7 in hypertrophic cardiomyopathy and dilated cardiomyopathy. Indian J Hum Genet, 2010, 16(2): 67-71.

[35] Purushotham G, Madhumohan K, Anwaruddin M, Nagarajaram H, Hariram V, Narasimhan C, Bashyam MD. The MYH7 p.R787H mutation causes hypertrophic cardiomyopathy in two unrelated families. Exp Clin Cardiol, 2010, 15(1): e1-e4.

[36] 王虎, 邹玉宝, 宋雷, 王继征, 孙凯, 宋晓东, 高硕, 张禅那, 惠汝太. 心脏肌球蛋白重链基因c.1273G》A突变与肥厚型心肌病的关联分析. 遗传, 2009, 31(5): 485-488.

[37] Winegrad S. Cardiac myosin binding protein C. Circ Res, 1999, 84(10): 1117-1126.

[38] Vikstrom KL, Leinwand LA. Contractile protein mutations and heart disease. Curr Opin Cell Biol, 1996, 8(1): 97-105.

[39] Oliva-Sandoval MJ, Ruiz-Espejo F, Monserrat L, Her-mida-Prieto M, Sabater M, Garcia-Molina E, Ortiz M, Rodriguez-Garcia MI, Núñez L, Gimeno JR, Castro-Beiras A, Valdés M. Insights into genotype-phenotype correlation in hypertrophic cardiomyopathy. Findings from 18 Spanish families with a single mutation in MYBPC3. Heart, 2010, 96(24): 1980-1984.

[40] Ehlermann P, Weichenhan D, Zehelein J, Steen H, Pribe R, Zeller R, Lehrke S, Zugck C, Ivandic BT, Katus HA. Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. BMC Med Genet, 2008, 9: 95.

[41] Perry SV. Troponin T: genetics, properties and function. J Muscle Res Cell Motil, 1998, 19(6): 575-602.

[42] Mayr JA, Merkel O, Kohlwein SD, Gebhardt BR, Böhles H, Fötschl U, Koch J, Jaksch M, Lochmüller H, Horváth R, Freisinger P, Sperl W. Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. Am J Hum Genet, 2007, 80(3): 478-484.

[43] Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang LB, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, Kim JB, Schmitt JP, Molkentin JD, Norris RA, Tager AM, Hoffman SR, Markwald RR, Seidman CE, Seidman JG. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J Clin Invest, 2010, 120(10): 3520-3529.

[44] Holmgren D, Wåhlander H, Eriksson BO, Oldfors A, Holme E, Tulinius M. Cardiomyopathy in children with mitochondrial disease; clinical course and cardiological findings. Eur Heart J, 2003, 24(3):280-288.

[45] Marin-Garcia J, Goldenthal MJ. Mitochondrial cardio-myopathy: molecular and biochemical analysis. Pediatr Cardiol, 1997, 18(4): 251-260.

[46] Taylor RW, Giordano C, Davidson MM, d'Amati G, Bain H, Hayes CM, Leonard H, Barron MJ, Casali C, Santorelli FM, Hirano M, Lightowlers RN, DiMauro S, Turnbull DM. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardio-myopathy. J Am Coll Cardiol, 2003, 41(10): 1786-1796.

[47] Manouvrier S, Rötig A, Hannebique G, Gheerbrandt JD, Royer-Legrain G, Munnich A, Parent M, Grünfeld JP, Largilliere C, Lombes A. Point mutation of the mitochondrial tRNA(Leu) gene (A 3243 G) in maternally inherited hypertrophic cardiomyopathy, diabetes mellitus, renal failure, and sensorineural deafness. J Med Genet, 1995, 32(8): 654-656.

[48] 齐建光, 张英, 威豫, 杨艳玲, 无晔, 姜玉武, 秦炯, 杜军保. 儿童线粒体病心脏损害23 例临床分析. 实用儿科临床杂志, 2006, 21(1): 12-13.

[49] Chen J, Hattori Y, Nakajima K, Eizawa T, Ehara T, Koyama M, Hirai T, Fukuda Y, Kinoshita M, Sugiyama A, Hayashi JI, Onaya T, Kobayashi T, Tawata M. Mitochondrial complex I activity is significantly decreased in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardio-myopathy associated with mitochondrial DNA C3310T muta-tion: a cybrid study. Diabetes Res Clin Pract, 2006, 74(2): 148-153.

[50] Merante F, Myint T, Tein I, Benson L, Robinson BH. An additional mitochondrial tRNAIle point mutation (A-to-G at nu-cleotide 4295) causing hypertrophic cardiomyopathy. Hum Mutat, 1996, 8(3): 216-222.

[51] Santorelli FM, Mak SC, Vazquezacevedo M, Gonzalezasti-azaran A, Ridaurasanz C, Gonzalezhalphen D, Dimauro S. A novel mitochondrial DNA point mutation associated with mitochondrial encephalocardiomyopathy. Biochem Biophys Res Commun, 1995, 216(3): 835-840.

[52] Akita Y, Koga Y, Iwanaga R, Wada N, Tsubone J, Fukuda S, Nakamura Y, Kato H. Fatal hypertrophic cardiomyopathy associated with an A8296G mutation in the mitochondrial tRNALys gene. Hum Mutat, 2000, 15(4): 382.

[53] Terasaki F, Tanaka M, Kawamura K, Kanzaki Y, Okabe M, Hayashi T, Shimomura H, Ito T, Suwa M, Gong JS, Zhang J, Kitaura Y. A case of cardiomyopathy showing progression from the hypertrophic to the dilated form: association of Mt8348A→G mutation in the mitochondrial tRNA(Lys) gene with severe ultrastructural alterations of mitochondria in cardiomyocytes. Jpn Circ J, 2001, 65(7): 691-694.

[54] Santorelli FM, Mak SC, El-Schahawi M, Casali C, Shanske S, Baram TZ, Madrid RE, DiMauro S. Maternally inherited cardiomyopathy and hearing loss associated with a novel muta-tion in the mitochondrial tRNALys gene (G8363A). Am J Hum Genet, 1996, 58(5): 933-939.

[55] Jonckheere AI, Hogeveen M, Nijtmans LGJ, van den Brand MAM, Janssen AJM, Diepstra JHS, van den Brandt FCA, van den Heuvel LP, Hol FA, Hofste TGJ, Kapusta L, Dillmann U, Shamdeen MG, Smeitink JAM, Rodenburg RJT. A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. J Med Genet, 2008, 45(3): 129-133.

[56] Pastores GM, Santorelli FM, Shanske S, Gelb BD, Fyfe B, Wolfe D, Willner JP. Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G). Am J Med Genet, 1994, 50(3): 265-271.

[57] Minieri M, Zingarelli M, Shubeita H, Vecchini A, Binaglia L, Carotenuto F, Fantini C, Fiaccavento R, Masuelli L, Coletti A, Simonelli L, Modesti A, Di Nardo P. Identification of a new missense mutation in the mtDNA of hereditary hypertrophic, but not dilated cardiomyopathic hamsters. Mol Cell Biochem, 2003, 252(1-2): 73-81.

[58] Merante F, Tein I, Benson L, Robinson BH. Maternally inherited hypertrophic cardiomyopathy due to a novel T-to-C transition at nucleotide 9997 in the mitochondrial tRNA(sup glycine) gene. Am J Hum Genet, 1994, 55(3): 437-446.

[59] Mimaki M, Ikota A, Sato A, Komaki H, Akanuma J, Nonaka I, Goto YI. A double mutation (G11778A and G12192A) in mitochondrial DNA associated with Leber's hereditary optic neuropathy and cardiomyopathy. J Hum Genet, 2003, 48(1): 47-50.

[60] Wang SB, Weng WC, Lee NC, Hwu WL, Fan PC, Lee WT. Mutation of mitochondrial DNA G13513A presenting with Leigh syndrome, Wolff-Parkinson-White syndrome and cardiomyopathy. Pediatr Neonatol, 2008, 49(4): 145-149.

[61] Valnot I, Kassis J, Chretien D, de Lonlay P, Parfait B, Mun-nich A, Kachaner J, Rustin P, Rötig A. A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reduc-tase (complex III) deficiency. Hum Genet, 1999, 104(6): 460-466.

[62] Obayashi T, Hattori K, Sugiyama S, Tanaka M, Tanaka T, Itoyama S, Deguchi H, Kawamura K, Koga Y, Toshima H, Takeda N, Nagano M, Ito T, Ozawa T. Point mutations in mitochondrial DNA in patients with hypertrophic cardio-myopathy. Am Heart J, 1992, 124(5): 1263-1269.

[63] 富路, 杨继红, 刘徽, 张淑华, 曲秀芬, 吴楠. 扩张型心肌病与线粒体DNA缺失片段的研究. 哈尔滨医科大学学报, 1996, 30(5): 436-438.

[64] 尹桂芝, 张丽容, 李殿富, 张林. 肥厚型心肌病患者心肌线粒体DNA 的大片段缺失. 南京铁道医学院学报, 1997, 16(4): 268-270.

[65] 尹桂芝, 张丽容, 李殿富, 张丽珊. 肥厚型心肌病患者心肌mtDNA大片段缺失的探讨. 遗传, 1999, 21(1): 16-18.

[66] 李文, 马沛然, 汪翼, 韩秀珍, 丘厚兴. 线粒体DNA点突变与心肌病关系的研究. 山东医药, 1998, 38(7): 3-4.

[67] 卢建菊, 陆惠玲. 线粒体DNA突变与心肌病关系的研究进展. 法医学杂志, 2001, 17(4): 242-243.

[68] Ishikawa K, Kimura S, Kobayashi A, Sato T, Matsumoto H, Ujiie Y, Nakazato K, Mitsugi M, Maruyama Y. Increased reactive oxygen species and anti-oxidative response in mitochondrial cardiomyopathy. Circ J, 2005, 69(5): 617-620.

[69] Tanaka T, Sohmiya K, Kawamura K. Is CD36 deficiency an etiology of hereditary hypertrophic cardiomyopathy? J Mol Cell Cardiol, 1997, 29(1): 121-127.

[70] Luedde M, Flögel U, Knorr M, Grundt C, Hippe HJ, Brors B, Frank D, Haselmann U, Antony C, Voelkers M, Schrader J, Most P, Lemmer B, Katus HA, Frey N. Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy. J Mol Med, 2009, 87(4): 411-422.

[71] Risch NJ. Searching for genetic determinants in the new mil-lennium. Nature, 2000, 405(6788): 847-856.

[72] Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ, Willey DL, Hunt SE, Cole CG, Coggill PC, Rice CM, Ning Z, Rogers J, Bentley DR, Kwok PY, Mardis ER, Yeh RT, Schultz B, Cook L, Davenport R, Dante M, Fulton L, Hillier L, Waterston RH, McPherson JD, Gilman B, Schaffner S, Van Etten WJ, Reich D, Higgins J, Daly MJ, Blumenstiel B, Baldwin J, Stange-Thomann N, Zody MC, Linton L, Lander ES, Altshuler D. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature, 2001, 409(6822): 928-933.

[73] Zhu XF, Bouzekri N, Southam L, Cooper RS, Adeyemo A, McKenzie CA, Luke A, Chen GJ, Elston RC, Ward R. Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet, 2001, 68(5): 1139-1148.

[74] Lechin M, Quiñones MA, Omran A, Hill R, Yu QT, Rakowski H, Wigle D, Liew CC, Sole M, Roberts R,Marian AJ. Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardio-myopathy. Circulation, 1995, 92(7): 1808-1812.

[75] Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation, 2001, 103(6): 789-791.

[76] Daw EW, Chen SN, Czernuszewicz G, Lombardi R, Lu Y, Ma JZ, Roberts R, Shete S, Marian AJ. Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy. Hum Mol Genet, 2007, 16(20): 2463-2471.

[77] Marian AJ. Modifier genes for hypertrophic cardiomyopathy. Curr Opin Cardiol, 2002, 17(3): 242-252.

[78] Abaci N, Gülec C, Bayrak F, Kömurcu Bayrak E, Kahveci G, Erginel Unaltuna N. The variations of BOP gene in hypertrophic cardiomyopathy. Anadolu Kardiyol Derg, 2010, 10(4): 303-309.

[79] Bayrak F, Kömurcü-Bayrak E, Mutlu B, Kahveci G, Erginel-Ünaltuna N. Genetic analysis of the Irx4 gene in hypertrophic cardiomyopathy. Turk Kardiyol Dern Ars, 2008, 36(2): 90-95.

[80] Friedrich FW, Bausero P, Sun YL, Treszl A, Krämer E, Juhr D, Richard P, Wegscheider K, Schwartz K, Brito D, Arbustini E, Waldenström A, Isnard R, Komajda M, Eschenha-gen T, Carrier L. A new polymorphism in human calmodulin III gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy. Eur Heart J, 2009, 30(13): 1648-1655.

[81] Coto E, Palacín M, Martín M, Castro MG, Reguero JR, García C, Berrazueta JR, Morís C, Morales B, Ortega F, Corao AI, Díaz M, Tavira B, Alvarez V. Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier. J Transl Med, 2010, 8: 64.

[82] Kaufman BD, Auerbach S, Reddy S, Manlhiot C, Deng LY, Prakash A, Printz BF, Gruber D, Papavassiliou DP, Hsu DT, Sehnert AJ, Chung WK, Mital S. RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy. Hum Genet, 2007, 122(5): 515-523.

[83] Zhao QS, Beck AJ, Vitale JM, Schneider JS, Chang C, Gao SM, Del Re D, Bhaumik M, Yehia G, Sadoshima J, Fraiden-raich D. Injection of wild type embryonic stem cells into Mst1 transgenic blastocysts prevents adult-onset cardio-myopathy. Stem Cell Rev, 2011, 7(2): 326-330.

[84] Fosslien E. Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation. Ann Clin Lab Sci, 2003, 33(4): 371-395.