cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLC10.15829/1728-8800-2013-1-88-94cardiovascular-125Research ArticleОБЗОРЫREVIEWSСЕРДЦЕ И ВОЗРАСТ (ЧАСТЬ I): ТЕОРИИ СТАРЕНИЯ, МОРФОЛОГИЧЕСКИЕ ИЗМЕНЕНИЯHEART AND AGE (PART I): AGEING THEORIES AND MORPHOLOGICAL CHANGESАкашеваД. У.AkashevaD. U.

с.н.с. отдела комплексного снижения риска неинфекционных заболеваний

dariga-akasheva@yandex.ruСтражескоИ. Д.StrazheskoI. D.

в.н.с. отдела

ДудинскаяЕ. Н.DudinskayaE. N.

с.н.с. отдела

НайденкоЕ. В.NaydenkoE. V.

аспирант

ТкачеваО. Н.TkachevaO. N.

руководитель отдела

ФГБУ «Государственный научно-исследовательский центр профилактической медицины» Минздрава России, МоскваState Research Centre for Preventive Medicine, Moscow2013200220131218894Copyright © Акашева Д.У., Стражеско И.Д., Дудинская Е.Н., Найденко Е.В., Ткачева О.Н., 20132013Акашева Д.У., Стражеско И.Д., Дудинская Е.Н., Найденко Е.В., Ткачева О.Н.Akasheva D.U., Strazhesko I.D., Dudinskaya E.N., Naydenko E.V., Tkacheva O.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/125

Старение сердца — сложный процесс, включающий множество клеточных и молекулярных изменений на клеточном и молекулярном уровнях и приводящих к формированию разных фенотипов старения внутри одного вида. Согласно теориям старения на молекулярно-генетическом уровне взаимодействуют несколько механизмов, включая соматические мутации, укорочение теломер, окислительный стресс и дефекты митохондрий. Наиболее признанные на сегодня теории старения, а также морфологические признаки старения сердца на клеточном, субклеточном и органном уровнях представлены в этой статье. 

Heart ageing is a complex process including multiple cellular and molecular-level changes and resulting in different ageing phenotypes within the same biological species. According to the existing ageing theories, the multiple interacting mechanisms of ageing include somatic mutations, telomere shortening, oxidative stress, and mitochondrial defects. The review presents the most accepted ageing theories and discusses morphological characteristics of heart ageing on subcellular, cellular, and organ levels.

старениепродолжительность жизнителомерыокислительный стрессапоптозageinglife expectancytelomeresoxidative stressapoptosisReferencesBurke A. Physiology and pathophysiology of poly (ADP-rebosyl) ation. Bioessays 2001; 23: 795–806.Burke A. Physiology and pathophysiology of poly (ADP-rebosyl) ation. Bioessays 2001; 23: 795–806.Karanjawala ZE, Lieber MR. DNA damage and aging. Mech Ageing Dev 2004; 125: 405–16.Karanjawala ZE, Lieber MR. DNA damage and aging. Mech Ageing Dev 2004; 125: 405–16.Melov S, Ravenscroft J, Malik S, et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science 2000; 289: 1567–9.Melov S, Ravenscroft J, Malik S, et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science 2000; 289: 1567–9.LeDoux SP, Wilson GL. Base excision repair of mitochondrial DNA damage in mammalian cells. Prog Nucleic Acid Res Mol Biol 2001; 68: 273–84.LeDoux SP, Wilson GL. Base excision repair of mitochondrial DNA damage in mammalian cells. Prog Nucleic Acid Res Mol Biol 2001; 68: 273–84.Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc 1972; 20: 145–7.Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc 1972; 20: 145–7.Bandy B, Davison AJ. Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Radic Biol Med 1990; 8 (6): 523–39.Bandy B, Davison AJ. Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Radic Biol Med 1990; 8 (6): 523–39.Jan Gruber, Sebastian Schaffer, Barry Halliwell. The mitochondrial free radical theory of ageing — Where do we stand? Frontiers in Bioscience 2008; 13: 6554–79.Jan Gruber, Sebastian Schaffer, Barry Halliwell. The mitochondrial free radical theory of ageing — Where do we stand? Frontiers in Bioscience 2008; 13: 6554–79.Suh JH, Heath SH, Hagen T. Two subpopulations of mitochondria in the aging rat heart display heterogenous levels of oxidative stress. Free Radic Biol Med 2003; 35: 1064–72.Suh JH, Heath SH, Hagen T. Two subpopulations of mitochondria in the aging rat heart display heterogenous levels of oxidative stress. Free Radic Biol Med 2003; 35: 1064–72.Ren J, Li Q, Wu S, Li SY, Babcock SA. Cardiac overexpression of antioxidant catalase attenuates aging-induce cardiomyocyte relaxation dysfunction. Mech Ageing Dev 2007; 128: 276–85.Ren J, Li Q, Wu S, Li SY, Babcock SA. Cardiac overexpression of antioxidant catalase attenuates aging-induce cardiomyocyte relaxation dysfunction. Mech Ageing Dev 2007; 128: 276–85.Van Raamsdonk JM, Hekimi S. Deletion of the Mitochondrial Superoxide Dismutase sod-2 Extends Lifespan in Caenorhabditis elegans, PLoS. Genetics 2009; 5: 1–13.Van Raamsdonk JM, Hekimi S. Deletion of the Mitochondrial Superoxide Dismutase sod-2 Extends Lifespan in Caenorhabditis elegans, PLoS. Genetics 2009; 5: 1–13.Lee CK, Pugh TD, Klopp RG, et al. The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med 2004; 36: 1043–57.Lee CK, Pugh TD, Klopp RG, et al. The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med 2004; 36: 1043–57.Seifried HE, Anderson DE, Fisher EI, Milner JA. A review of the interaction among dietary antioxidants and reactive oxygen species. J Nutr Biochem 2007; 18: 567–79.Seifried HE, Anderson DE, Fisher EI, Milner JA. A review of the interaction among dietary antioxidants and reactive oxygen species. J Nutr Biochem 2007; 18: 567–79.Scott BC, Aruoma OI, Evans PJ, et al. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic Res 1994; 20: 119–33.Scott BC, Aruoma OI, Evans PJ, et al. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic Res 1994; 20: 119–33.José Marín-García. Aging and the Heart. A Post-Genomic View. Springer 2008; 16–8.José Marín-García. Aging and the Heart. A Post-Genomic View. Springer 2008; 16–8.Olovnikov AM. Telomeres, telomerase, and aging: origin of the theory. Exp Gerontol 1996; 31 (4): 443–8.Olovnikov AM. Telomeres, telomerase, and aging: origin of the theory. Exp Gerontol 1996; 31 (4): 443–8.Young AT, Lakey JR, Murray AG, et al. In vitro senescence occurring in normal human endothelial cells can be rescued by ectopic telomerase activity. Transplant Proc 2003; 35: 2483–5.Young AT, Lakey JR, Murray AG, et al. In vitro senescence occurring in normal human endothelial cells can be rescued by ectopic telomerase activity. Transplant Proc 2003; 35: 2483–5.Judin V. Long or a short … or the Nobel Prize for the future of immortality. Ezhenedel’nik Apteca 2009; 49: 720. Russian (Юдин В. Долго ли, коротко ли…, или Нобелевская премия за будущее бессмертие. Еженедельник АПТЕКА 2009; 49: 720).Judin V. Long or a short … or the Nobel Prize for the future of immortality. Ezhenedel’nik Apteca 2009; 49: 720. Russian (Юдин В. Долго ли, коротко ли…, или Нобелевская премия за будущее бессмертие. Еженедельник АПТЕКА 2009; 49: 720).Collerton J, Martin-Ruiz C, Kenny A, et al. Telomere length is associated with left ventricular function in the oldest old: the Newcastle 85+ study. Eur Heart J 2007; 28: 172–6.Collerton J, Martin-Ruiz C, Kenny A, et al. Telomere length is associated with left ventricular function in the oldest old: the Newcastle 85+ study. Eur Heart J 2007; 28: 172–6.Serra V, von Zglinicki T, Lorenz M, Saretzki G. Extracellular superoxide dismutase is a major antioxidant in human fibroblasts and slows telomere shortening. J Biol Chem 2003; 278: 6824–30.Serra V, von Zglinicki T, Lorenz M, Saretzki G. Extracellular superoxide dismutase is a major antioxidant in human fibroblasts and slows telomere shortening. J Biol Chem 2003; 278: 6824–30.Oikawa S, Tada-Oikawa S, Kawanishi S. Site-specific DNA damage at the GGG sequence by UVA involves acceleration of telomere shortening. Biochemistry 2001; 40: 4763–8.Oikawa S, Tada-Oikawa S, Kawanishi S. Site-specific DNA damage at the GGG sequence by UVA involves acceleration of telomere shortening. Biochemistry 2001; 40: 4763–8.Valdes AM, Andrew T, Gardner JP, et al. Obesity, cigarette smoking, and telomere length in women. Lancet 2005; 366: 662–4.Valdes AM, Andrew T, Gardner JP, et al. Obesity, cigarette smoking, and telomere length in women. Lancet 2005; 366: 662–4.Matthews C, Gorenne I, Scott S, et al. Vascular smoothmuscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidativestress. Circ Res 2006; 99: 156–64.Matthews C, Gorenne I, Scott S, et al. Vascular smoothmuscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidativestress. Circ Res 2006; 99: 156–64.Mikhail V. Blagosklonny. Impact papers on aging in 2009. Aging, marh 2010; 2 (3).Mikhail V. Blagosklonny. Impact papers on aging in 2009. Aging, marh 2010; 2 (3).Bryan TM, Englezou A, Gupta J, et al. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 1995; 14 (17): 4240–8.Bryan TM, Englezou A, Gupta J, et al. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 1995; 14 (17): 4240–8.Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281: 1322–6.Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281: 1322–6.Chumakov PM. The p-53 protein: universal functions in a multicellular organism. M.: Uspehi biologicheskoj himii 2007; 47: 3–52. Russian (Чумаков П.М. Белок р53 и его универсальные функции в многокле- точном организме. М.: Успехи биологической химии 2007; 47: 3–52).Chumakov PM. The p-53 protein: universal functions in a multicellular organism. M.: Uspehi biologicheskoj himii 2007; 47: 3–52. Russian (Чумаков П.М. Белок р53 и его универсальные функции в многокле- точном организме. М.: Успехи биологической химии 2007; 47: 3–52).Shabalin AV, Voevoda MI. Longevity — a model study of the aging process. “Bjulleten’” SO RAMN 2006; 4; 11–21. Russian (Шабалин А.В., Воевода М.И. Долгожительство — модель изучения процесса старения. БЮЛЛЕТЕНЬ СО РАМН 2006; 4; 11–21).Shabalin AV, Voevoda MI. Longevity — a model study of the aging process. “Bjulleten’” SO RAMN 2006; 4; 11–21. Russian (Шабалин А.В., Воевода М.И. Долгожительство — модель изучения процесса старения. БЮЛЛЕТЕНЬ СО РАМН 2006; 4; 11–21).Kervinen K, Savolainen MJ, Salokannel J, et al. Apolipoprotein E and B polymorphisms — longevity factors assessed in nonagenarians. Atherosclerosis 1994; 105: 89–95.Kervinen K, Savolainen MJ, Salokannel J, et al. Apolipoprotein E and B polymorphisms — longevity factors assessed in nonagenarians. Atherosclerosis 1994; 105: 89–95.Candore G, Aquino A, Balistreri CR, et al. Inflammation, longevity, and cardiovascular diseases: role of polymorphisms of TLR4. Ann N Y Acad Sci 2006; 1067: 282–7.Candore G, Aquino A, Balistreri CR, et al. Inflammation, longevity, and cardiovascular diseases: role of polymorphisms of TLR4. Ann N Y Acad Sci 2006; 1067: 282–7.Skulachev VP. The aging. Biohimija 1997; 62: 1394–9. Russian (Скулачев В.П. Старение организма. Биохимия 1997; 62: 1394–9.Skulachev VP. The aging. Biohimija 1997; 62: 1394–9. Russian (Скулачев В.П. Старение организма. Биохимия 1997; 62: 1394–9.Baryshnikov AJu, Shishkin JuV. Immunological problems of apoptosis. M.: Jeditorial URSS 2002; 320 p. Russian (Барышников А.Ю., Шишкин Ю.В. Иммунологические проблемы апоптоза. М.: Эдиториал УРСС 2002; 320 c).Baryshnikov AJu, Shishkin JuV. Immunological problems of apoptosis. M.: Jeditorial URSS 2002; 320 p. Russian (Барышников А.Ю., Шишкин Ю.В. Иммунологические проблемы апоптоза. М.: Эдиториал УРСС 2002; 320 c).Scorrano L, Ashiya M, Buttle K, et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2002; 2: 55–67.Scorrano L, Ashiya M, Buttle K, et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2002; 2: 55–67.Kujoth GC, Hiona A, Pugh TD, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2005; 309: 481–4.Kujoth GC, Hiona A, Pugh TD, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2005; 309: 481–4.Abdrashitova AT, Belolapenko IA, Panova TN. Dysregulation of apoptosis in aging. Astrahanskij medicinskij zhurnal 2010; 2: 26–31. Russian (Абдрашитова А.Т., Белолапенко И.А., Панова Т.Н. Нарушение регу- ляции апоптоза при старении. Астраханский медицинский журнал 2010; 2: 26–31).Abdrashitova AT, Belolapenko IA, Panova TN. Dysregulation of apoptosis in aging. Astrahanskij medicinskij zhurnal 2010; 2: 26–31. Russian (Абдрашитова А.Т., Белолапенко И.А., Панова Т.Н. Нарушение регу- ляции апоптоза при старении. Астраханский медицинский журнал 2010; 2: 26–31).Long X, Goldenthal MJ, Wu GM, Mar n-Garc a J. Mitochondrial Ca2+ flux and respiratory enzyme activity decline are early events in cardiomyocyte response to H2O2. J Mol Cell Cardiol 2004; 37: 63–70.Long X, Goldenthal MJ, Wu GM, Mar n-Garc a J. Mitochondrial Ca2+ flux and respiratory enzyme activity decline are early events in cardiomyocyte response to H2O2. J Mol Cell Cardiol 2004; 37: 63–70.Zajnullin VG, Moskalev AA, Shaposhnikov MV, Taskaev AI. Modern aspects of radiobiology Drosophila melanogaster. Apoptosis and aging. Radiojekologija 1999; 39 (1): 49–57. Russian (Зайнуллин В.Г., Москалев А.А., Шапошников М.В., Таскаев А.И. Современные аспек- ты радиобиологии Drosophila melanogaster. Апоптоз и старение. Радиоэкология 1999; 39 (1): 49–57).Zajnullin VG, Moskalev AA, Shaposhnikov MV, Taskaev AI. Modern aspects of radiobiology Drosophila melanogaster. Apoptosis and aging. Radiojekologija 1999; 39 (1): 49–57. Russian (Зайнуллин В.Г., Москалев А.А., Шапошников М.В., Таскаев А.И. Современные аспек- ты радиобиологии Drosophila melanogaster. Апоптоз и старение. Радиоэкология 1999; 39 (1): 49–57).Orsini F, Migliaccio E, Moroni M, et al. The life span determinant p66 Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem 2004; 279: 25689–95.Orsini F, Migliaccio E, Moroni M, et al. The life span determinant p66 Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem 2004; 279: 25689–95.Dil’man VM. The large biologic clock. M.: Znanie 1981; 207 p. Russian (Дильман В. М. Большие биологические часы. М.: Знание 1981; 207 c).Dil’man VM. The large biologic clock. M.: Znanie 1981; 207 p. Russian (Дильман В. М. Большие биологические часы. М.: Знание 1981; 207 c).Thomas BL. Kirkwood. Understanding the Odd Science of Aging. Cell 2005; 120: 437–47.Thomas BL. Kirkwood. Understanding the Odd Science of Aging. Cell 2005; 120: 437–47.Reiser KM. Influence of age and long-term dietary restriction on enzymatically mediated crosslinks and nonenzymaticglycation of collagen in mice. J Gerontol 1994; 49: B71–9.Reiser KM. Influence of age and long-term dietary restriction on enzymatically mediated crosslinks and nonenzymaticglycation of collagen in mice. J Gerontol 1994; 49: B71–9.Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 1991; 68: 1560–8.Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 1991; 68: 1560–8.Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98–102.Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98–102.Dimmeler S, Leri A. Aging and disease as modifiers of efficacy of cell therapy. Circ Res 2008; 102: 1319–30.Dimmeler S, Leri A. Aging and disease as modifiers of efficacy of cell therapy. Circ Res 2008; 102: 1319–30.Kissel CK, Lehmann R, Assmus B, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with post infarction heart failure. JACC 2007; 49: 2341–9.Kissel CK, Lehmann R, Assmus B, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with post infarction heart failure. JACC 2007; 49: 2341–9.Schmidt-Lucke C, Rossig L, Fichtlscherer S, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005; 111: 2981–7.Schmidt-Lucke C, Rossig L, Fichtlscherer S, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005; 111: 2981–7.Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005; 353: 999–1007.Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005; 353: 999–1007.Valgimigli M, Rigolin GM, Fucili A, et al. CD34_ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation 2004; 110: 1209–12.Valgimigli M, Rigolin GM, Fucili A, et al. CD34_ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation 2004; 110: 1209–12.Leone AM, Rutella S, Bonanno G, et al. Mobilization of bone marrow￾derived stem cells after myocardial infarction and left ventricular function. Eur Heart J 2005; 26: 1196–204.Leone AM, Rutella S, Bonanno G, et al. Mobilization of bone marrow￾derived stem cells after myocardial infarction and left ventricular function. Eur Heart J 2005; 26: 1196–204.Terman A, Brunk UT. Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 2005; 68: 355–65.Terman A, Brunk UT. Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 2005; 68: 355–65.Terman A, Dalen H, Eaton JW, et al. Aging of cardiac myocytes in culture: oxidative stress, lipofuscin accumulation, and mitochondrial turnover. Ann NY Acad Sci 2004; 1019: 70–7.Terman A, Dalen H, Eaton JW, et al. Aging of cardiac myocytes in culture: oxidative stress, lipofuscin accumulation, and mitochondrial turnover. Ann NY Acad Sci 2004; 1019: 70–7.Terman A, Dalen H, Brunk UT. Ceroid/lipofuscin-loaded human fibroblasts show decreased survival time and diminished autophagocytosis during amino acid starvation. Exp Gerontol 1999; 34: 943–57.Terman A, Dalen H, Brunk UT. Ceroid/lipofuscin-loaded human fibroblasts show decreased survival time and diminished autophagocytosis during amino acid starvation. Exp Gerontol 1999; 34: 943–57.Josephson IR, Guia A, Stern MD, et al. Alterations in properties of L-type Ca channels in aging rat heart. J Mol Cell Cardiol 2002; 34: 297–308.Josephson IR, Guia A, Stern MD, et al. Alterations in properties of L-type Ca channels in aging rat heart. J Mol Cell Cardiol 2002; 34: 297–308.Lakatta EG. Cellular and Molecular Clues to Heart and Arterial Aging. Circulation 2003; 107: 490–7.Lakatta EG. Cellular and Molecular Clues to Heart and Arterial Aging. Circulation 2003; 107: 490–7.Pollack M, Phaneuf S, Dirks A, Leeuwenburgh C. The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann NY Acad Sci 2002; 959: 93–107.Pollack M, Phaneuf S, Dirks A, Leeuwenburgh C. The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann NY Acad Sci 2002; 959: 93–107.Manabe I, Shindo T, Nagai R. Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy. Circ Res 2002; 91: 1103–13.Manabe I, Shindo T, Nagai R. Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy. Circ Res 2002; 91: 1103–13.Burlew BS. Diastolic dysfunction in the elderly — the interstitial issue. Am J Geriatr Cardiol 2004; 13: 29–38.Burlew BS. Diastolic dysfunction in the elderly — the interstitial issue. Am J Geriatr Cardiol 2004; 13: 29–38.Stritzke J, Ricardo M, Marcus P, Duderstadt S. The Aging Process of the Heart: Obesity Is the Main Risk Factor for Left Atrial Enlargement DuringAgin. JACC 2009; 54: 1982–9.Stritzke J, Ricardo M, Marcus P, Duderstadt S. The Aging Process of the Heart: Obesity Is the Main Risk Factor for Left Atrial Enlargement DuringAgin. JACC 2009; 54: 1982–9.Sun Y, Weber KT. RAS and connective tissue in the heart. Int J Biochem Cell Biol 2003; 35: 919–31.Sun Y, Weber KT. RAS and connective tissue in the heart. Int J Biochem Cell Biol 2003; 35: 919–31.Allessie M, Schotten U, Verheule S, Harks E. Gene therapy for repair of cardiac fibrosis: a long way to Tipperary. Circulation 2005; 111: 391–3.Allessie M, Schotten U, Verheule S, Harks E. Gene therapy for repair of cardiac fibrosis: a long way to Tipperary. Circulation 2005; 111: 391–3.Rehman HU. Age and the cardiovascular system. Hosp Med 1999; 60: 645–52.Rehman HU. Age and the cardiovascular system. Hosp Med 1999; 60: 645–52.Kawamura S, Takahashi M, Ishihara T, Uchino F. Incidence and distribution of isolated atrial amyloid: histologic and immunohistochemical studies of 100 aging hearts. PatholInt 1995; 45: 335–42.Kawamura S, Takahashi M, Ishihara T, Uchino F. Incidence and distribution of isolated atrial amyloid: histologic and immunohistochemical studies of 100 aging hearts. PatholInt 1995; 45: 335–42.Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 1996; 101: 395–400.Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 1996; 101: 395–400.Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 2004; 286: E686–96.Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 2004; 286: E686–96.Barasch E, Gottdiener JS, Larsen EK, et al. Clinical significance of calcification of the fibrous skeleton of the heart and aortosclerosis in community dwelling elderly. The Cardiovascular Health Study (CHS). Am Heart J 2006; 151: 39–47.Barasch E, Gottdiener JS, Larsen EK, et al. Clinical significance of calcification of the fibrous skeleton of the heart and aortosclerosis in community dwelling elderly. The Cardiovascular Health Study (CHS). Am Heart J 2006; 151: 39–47.

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