russjcardiolРоссийский кардиологический журналRussian Journal of Cardiology1560-40712618-7620«SILICEA-POLIGRAF» LLC10.15829/1560-4071-2014-5-35-42russjcardiol-67Research ArticleМИОКАРДИТЫ, КЛАПАННЫЕ И НЕКОРОНАРОГЕННЫЕ ЗАБОЛЕВАНИЯMYOCARDITISES, VALVULAR AND NONCORONAROGENIC DISEASESГИПЕРТРОФИЧЕСКАЯ КАРДИОМИОПАТИЯ: ГЕНЕТИЧЕСКИЕ ИЗМЕНЕНИЯ, ПАТОГЕНЕЗ И ПАТОФИЗИОЛОГИЯHYPERTROPHIC CARDIOMYOPATHY: GENETIC ALTERATIONS, PATHOGENESIS AND PATHOPHYSIOLOGYВатутинН. Т.VatutinN. T.

д. м.н., профессор, заведующий кафедрой внутренней медицины № 1

ТарадинГ. Г.TaradinG. G.

к. м.н., доцент кафедры внутренней медицины № 1

taradin@inbox.ruМаронМ. С.MaronM. S.

Assistant Professor, Director of Hypertrophic Cardiomyopathy Center

Донецкий национальный медицинский университет им. М. Горького, Донецк, УкраинаУкраинаDonetsk State Medical University n.a. M. Gorkiy, Donetsk, UkraineUkraineTuft University School of Medicine, Hypertrophic Cardiomyopathy Center, Boston, Massachusetts, USAСоединённые Штаты АмерикиTuft University School of Medicine, Hypertrophic Cardiomyopathy Center, Boston, Massachusetts, USAUnited States201428052014053542Copyright © Ватутин Н.Т., Тарадин Г.Г., Марон М.С., 20142014Ватутин Н.Т., Тарадин Г.Г., Марон М.С.Vatutin N.T., Taradin G.G., Maron M.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://russjcardiol.elpub.ru/jour/article/view/67

Настоящий обзор посвящен описанию генетических изменений, патогенетических механизмов и патофизиологии гипертрофической кардиомиопатии на основе анализа последних опубликованных данных. Приведены современные данные о роли выявленных многочисленных мутаций структурных, сократительных и регуляторных белков саркомера в патогенезе кардиомиопатии. Освещены основные гипотезы патогенетического процесса, особое внимание уделено нарушению регуляции обмена кальция. Подчеркнута важность проведения генетического тестирования у больных гипертрофической кардиомиопатией и их родственников. В обзоре обсуждаются основные патофизиологические характеристики заболевания с позиции их диагностической, клинической и прогностической значимости. Кроме описания патофизиологических особенностей, в частности, обструкции выносящего тракта левого желудочка, диастолической дисфункции, ишемии миокарда и нарушений ритма сердца, подчеркнута взаимосвязь этих нарушений с клинической картиной, а также роль современных методов исследования (позитронно-эмиссионная и компьютерная томография) в ранней диагностике и мониторировании клинического течения заболевания.

 

 

 

 

 

 

The review is dedicated to the description of genetic alterations, pathogenetic mechanisms and pathophysiology of hypertrophic cardiomyopathy, based on the analysis of current up to date information. A contemporary data is provided on the role a plenty discovered mutations of structural, contractile and regulatory sarcomere proteins in cardiomyopathy. The main hypotheses of pathogenetic processes are highlighted, especially the disordered calcium exchange. The importance of genetic testing of patients with hypertrophic cardiomyopathy and their relatives is underlined.

The review concerns the basic pathophysiologic characteristics of the disease according to their diagnostic, clinical and prognostic value. Except the description of pathophysiologic properties, as a matter of fact, the obstruction of outflow in the left ventricle, diastolic dysfunction, myocardial ischemia and rhythm disorders, the contemporary instrumental diagnostic methods (positron-emission tomography, computed tomography) in early diagnostic and monitoring of the disease.

гипертрофическая кардиомиопатиягенетические мутациипатогенезпатофизиологияhypertrophic cardiomyopathygenetic mutationspathogenesispathophysiologyReferencesMaron BJ, Gardin JM, Flack JM, et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiography analysis of 4111 subjects in the CARDIA study Coronary Artery Risk Development in (Young) Adults. Circulation. 1995; 92: 785-9.Maron BJ, Gardin JM, Flack JM, et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiography analysis of 4111 subjects in the CARDIA study Coronary Artery Risk Development in (Young) Adults. Circulation. 1995; 92: 785-9.Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/ European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force onMaron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/ European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force onClinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J. Amer. Coll. Cardiol. 2003; 42 (9): 1687-713.Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J. Amer. Coll. Cardiol. 2003; 42 (9): 1687-713.Maron BJ, Seidman CE, Ackerman MJ, et al. What's in a name? Dilemmas in nomenclature characterizing hypertrophic cardiomyopathy and left ventricular hypertrophy. Circ. Cardiovasc. Genet. 2009; 2: 81-6.Maron BJ, Seidman CE, Ackerman MJ, et al. What's in a name? Dilemmas in nomenclature characterizing hypertrophic cardiomyopathy and left ventricular hypertrophy. Circ. Cardiovasc. Genet. 2009; 2: 81-6.Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. A report of the American College of CardiologyGersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. A report of the American College of CardiologyFoundation/American Heart Association Task Force on Practice Guidelines. J. Amer. Coll. Cardiol. 2011; 58 (25): 2703-38.Foundation/American Heart Association Task Force on Practice Guidelines. J. Amer. Coll. Cardiol. 2011; 58 (25): 2703-38.Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J. Amer. Coll. Cardiol. 2012; 60 (8): 705-15.Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J. Amer. Coll. Cardiol. 2012; 60 (8): 705-15.Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013; 381 (9862): 242-55.Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013; 381 (9862): 242-55.Ho CY. Hypertrophic cardiomyopathy: preclinical and early phenotype. J. Cardiovasc. Trans. Res. 2009; 2: 462-70.Ho CY. Hypertrophic cardiomyopathy: preclinical and early phenotype. J. Cardiovasc. Trans. Res. 2009; 2: 462-70.Ingles J, McGaughran J, Scuffham P, et al. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart. 2012; 98: 625-30.Ingles J, McGaughran J, Scuffham P, et al. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart. 2012; 98: 625-30.Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy. New Engl. J. Med. 1990; 62: 999-1006.Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy. New Engl. J. Med. 1990; 62: 999-1006.Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J. Amer. Coll. Cardiol. 2009; 54: 201-11.Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J. Amer. Coll. Cardiol. 2009; 54: 201-11.Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy. Circulation. 2010; 122: 2441-9.Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy. Circulation. 2010; 122: 2441-9.Ho CY Hypertrophic cardiomyopathy in 2012. Circulation. 2012; 125: 1432-8.Ho CY Hypertrophic cardiomyopathy in 2012. Circulation. 2012; 125: 1432-8.Lopes LR, Zekavati A, Syrris P, et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J. Med. Gen. 2013; 50 (4): 228-39.Lopes LR, Zekavati A, Syrris P, et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J. Med. Gen. 2013; 50 (4): 228-39.Konno T, Chang S, Seidman JG, et al. Genetics of hypertrophic cardiomyopathy. Curr. Opin. Cardiol. 2010; 25 (3): 205-9.Konno T, Chang S, Seidman JG, et al. Genetics of hypertrophic cardiomyopathy. Curr. Opin. Cardiol. 2010; 25 (3): 205-9.Pasquale F, Syrris P, Kaski JP, et al. Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene. Circ. Cardiovasc. Genet. 2012; 5 (1): 10-17.Pasquale F, Syrris P, Kaski JP, et al. Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene. Circ. Cardiovasc. Genet. 2012; 5 (1): 10-17.Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin. Proc. 2008; 83: 630-8.Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin. Proc. 2008; 83: 630-8.Girolami F, Ho CY Semsarian C, et al. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J. Amer. Coll. Cardiol. 2010; 55 (14): 1444-53.Girolami F, Ho CY Semsarian C, et al. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J. Amer. Coll. Cardiol. 2010; 55 (14): 1444-53.Ruggiero A, Chen SN, Lombardi R, et al. Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. Cardiovasc. Res. 2013;97:44-54.Ruggiero A, Chen SN, Lombardi R, et al. Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. Cardiovasc. Res. 2013;97:44-54.Christiaans I, Van Engelen K, Van Langen IM, et al. Risk stratification for sudden death in hypertrophic cardiomyopathy: systematic review of clinical risk markers. Europace. 2010; 12:313-21.Christiaans I, Van Engelen K, Van Langen IM, et al. Risk stratification for sudden death in hypertrophic cardiomyopathy: systematic review of clinical risk markers. Europace. 2010; 12:313-21.McKeown P, Muir AR. Risk assessment in hypertrophic cardiomyopathy: contemporary guidelines hampered by insufcient evidence. Heart. 2013; 99 (8): 511-2.McKeown P, Muir AR. Risk assessment in hypertrophic cardiomyopathy: contemporary guidelines hampered by insufcient evidence. Heart. 2013; 99 (8): 511-2.Olivotto I, Cecchi F, Poggesi C, et al. Patterns of disease progression in hypertrophic cardiomyopathy: an individualized approach to clinical setting. Circ. Heart Fail. 2012; 5: 535-46.Olivotto I, Cecchi F, Poggesi C, et al. Patterns of disease progression in hypertrophic cardiomyopathy: an individualized approach to clinical setting. Circ. Heart Fail. 2012; 5: 535-46.Marston S, Copeland O, Jacques A, et al. Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circ. Res. 2009; 105: 219-22.Marston S, Copeland O, Jacques A, et al. Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circ. Res. 2009; 105: 219-22.Guinto PJ, Haim TE, Dowell-Martino CC, et al. Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models. Amer. J. Physiol. Heart Circ. Physiol. 2009; 297: H614-H626.Guinto PJ, Haim TE, Dowell-Martino CC, et al. Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models. Amer. J. Physiol. Heart Circ. Physiol. 2009; 297: H614-H626.Lan F, Lee AS, Liang P, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013; 12 (1): 101-13.Lan F, Lee AS, Liang P, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013; 12 (1): 101-13.Baudenbacher F, Schober T, Pinto JR, et al. Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J. Clin. Invest. 2008; 118: 3893-903.Baudenbacher F, Schober T, Pinto JR, et al. Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J. Clin. Invest. 2008; 118: 3893-903.Lombardi R, Rodriguez G, Chen SN, et al. Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms. Circulation. 2009;119: 1398-407.Lombardi R, Rodriguez G, Chen SN, et al. Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms. Circulation. 2009;119: 1398-407.Backs J, Backs T, Neef S, et al. The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc. Nat. Acad. Sci. USA. 2009; 106: 2342-7.Backs J, Backs T, Neef S, et al. The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc. Nat. Acad. Sci. USA. 2009; 106: 2342-7.Ashrafian H, McKenna WJ, Watkins H. Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy. Circ. Res. 2011; 109: 86-96.Ashrafian H, McKenna WJ, Watkins H. Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy. Circ. Res. 2011; 109: 86-96.Tardiff JC. Sarcomeric proteins and familial hypertrophic cardiomyopathy: linking mutations in structural proteins to complex cardiovascular phenotypes. Heart Fail. Rev. 2005; 10: 237-48.Tardiff JC. Sarcomeric proteins and familial hypertrophic cardiomyopathy: linking mutations in structural proteins to complex cardiovascular phenotypes. Heart Fail. Rev. 2005; 10: 237-48.Watkins H, Ashrafian H, McKenna WJ. The genetics of hypertrophic cardiomyopathy: Teare redux. Heart. 2008; 94: 1264-8.Watkins H, Ashrafian H, McKenna WJ. The genetics of hypertrophic cardiomyopathy: Teare redux. Heart. 2008; 94: 1264-8.Ashrafian H, Redwood C, Blair E, et al. Hypertrophic cardiomyopathy: a paradigm for myocardial energy depletion. Trends Genet. 2003; 19: 263-8.Ashrafian H, Redwood C, Blair E, et al. Hypertrophic cardiomyopathy: a paradigm for myocardial energy depletion. Trends Genet. 2003; 19: 263-8.Cambronero F, Marin F, Roldan V, et al. Biomarkers of pathophysiology: implications for clinical management and prognosis. Eur. Heart J. 2009; 30: 139-51.Cambronero F, Marin F, Roldan V, et al. Biomarkers of pathophysiology: implications for clinical management and prognosis. Eur. Heart J. 2009; 30: 139-51.Crilley JG, Boehm EA, Blair E, et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J. Amer. Coll. Cardiol. 2003; 41: 1776-82.Crilley JG, Boehm EA, Blair E, et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J. Amer. Coll. Cardiol. 2003; 41: 1776-82.Wang L, Seidman JG, Seidman CE. Harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann. Intern. Med. 2010; 152 (8): 513-20.Wang L, Seidman JG, Seidman CE. Harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann. Intern. Med. 2010; 152 (8): 513-20.Ho CY. Genetics and clinical destiny: improving care in hypertrophic cardiomyopathy. Circulation. 2010; 122: 2430-40.Ho CY. Genetics and clinical destiny: improving care in hypertrophic cardiomyopathy. Circulation. 2010; 122: 2430-40.Muir AR, Menown IBA. Genetic biomarkers in cardiovascular disease. Biomarkers Med. 2013; 7 (4): 497-9.Muir AR, Menown IBA. Genetic biomarkers in cardiovascular disease. Biomarkers Med. 2013; 7 (4): 497-9.Coats CJ, Elliott PM. Genetic biomarkers in hypertrophic cardiomyopathy. Biomarkers Med. 2013; 7 (4): 505-16.Coats CJ, Elliott PM. Genetic biomarkers in hypertrophic cardiomyopathy. Biomarkers Med. 2013; 7 (4): 505-16.Charron P. Genetic analysis for predictive screening in hypertrophic cardiomyopathy. Heart. 2012; 98 (8): 603-4.Charron P. Genetic analysis for predictive screening in hypertrophic cardiomyopathy. Heart. 2012; 98 (8): 603-4.Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ. Research. 2011; 108: 743-50.Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ. Research. 2011; 108: 743-50.Poliac LC, Barron ME, Maron BJ. Hypertrophic cardiomyopathy. Anesthesiology. 2006; 104 (1): 183-92.Poliac LC, Barron ME, Maron BJ. Hypertrophic cardiomyopathy. Anesthesiology. 2006; 104 (1): 183-92.Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular out ow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. New Engl. J. Med. 2003; 348: 295-303.Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular out ow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. New Engl. J. Med. 2003; 348: 295-303.Maron BJ. Hypertrophic cardiomyopathy. In: Braunwald's Heart Disease: a Textbook of Cardiovascular Medicine, 8th ed. Ed. by: P. Libby, R. O. Bonow, D. L. Mann, D.P. Zipes eds. Philadelphia, PA, WB Saunders. 2007; 65: 1763-89.Maron BJ. Hypertrophic cardiomyopathy. In: Braunwald's Heart Disease: a Textbook of Cardiovascular Medicine, 8th ed. Ed. by: P. Libby, R. O. Bonow, D. L. Mann, D.P. Zipes eds. Philadelphia, PA, WB Saunders. 2007; 65: 1763-89.Maron MS, Olivotto I, Zenovich A, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006; 114: 2232-9.Maron MS, Olivotto I, Zenovich A, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006; 114: 2232-9.Ten Berg J, Steggerda RC, Siebelink HMJ. The patient with hypertrophic cardiomyopathy. Heart. 2010; 96: 1764-72.Ten Berg J, Steggerda RC, Siebelink HMJ. The patient with hypertrophic cardiomyopathy. Heart. 2010; 96: 1764-72.Maron MS, Olivotto I, Maron BJ, et al. The case for myocardial ischemia in hypertrophic cardiomyopathy. J. Amer. Coll. Cardiol. 2009; 54: 866-75.Maron MS, Olivotto I, Maron BJ, et al. The case for myocardial ischemia in hypertrophic cardiomyopathy. J. Amer. Coll. Cardiol. 2009; 54: 866-75.Olivotto I, Cecchi F, Camici PG. Coronary microvascular dysfunction and ischemia in hypertrophic cardiomyopathy. Mechanisms and clinical consequences. Ital. Heart J. 2004; 5: 572-80.Olivotto I, Cecchi F, Camici PG. Coronary microvascular dysfunction and ischemia in hypertrophic cardiomyopathy. Mechanisms and clinical consequences. Ital. Heart J. 2004; 5: 572-80.Petersen SE, Jerosch-Herold M, Hudsmith LE, et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation. 2007; 115: 2418-25.Petersen SE, Jerosch-Herold M, Hudsmith LE, et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation. 2007; 115: 2418-25.Bravo PE, Pinheiro A, Higuchi T, et al. PET/CT assessment of symptomatic individuals with obstructive and nonobstructive hypertrophic cardiomyopathy. J. Nucl. Med. 2012; 53: 407-14.Bravo PE, Pinheiro A, Higuchi T, et al. PET/CT assessment of symptomatic individuals with obstructive and nonobstructive hypertrophic cardiomyopathy. J. Nucl. Med. 2012; 53: 407-14.Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy. J. Amer. Coll. Cardiol. 2008; 51: 1369-74.Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy. J. Amer. Coll. Cardiol. 2008; 51: 1369-74.Gu S, Liu Z, Liu Z. Prevalence and related factors of arrhythmias in patients with hypertrophic cardiomyopathy. Heart. 2012; 98 (Suppl. 2): E248-E249.Gu S, Liu Z, Liu Z. Prevalence and related factors of arrhythmias in patients with hypertrophic cardiomyopathy. Heart. 2012; 98 (Suppl. 2): E248-E249.

The authors declare that there are no conflicts of interest present.