Advertisement

Calcium-Handling Defects and Changes in Cardiac Function in the Aging Heart

  • Adriana Adameova
  • Nirankar S. Neki
  • Paramjit S. Tappia
  • Naranjan S. Dhalla
Chapter

Abstract

Individuals aged 70 years or older represent a major population group with a higher risk for myocardial infarction and heart failure. A wide variety of factors have been considered to underlie the phenotype of the aging heart; however, alterations in Ca 2+-handling appear to be of critical importance in the progression of heart dysfunction due to aging. In fact, changes in gene expression, protein content, and activity of the Ca2+-handling proteins such as sarcolemmal (SL) Ca2+-channels and Na+–Ca2+ exchanger as well as sarcoplasmic reticular Ca2+-pump and Ca2+-release channels have been reported in aging hearts. These defects in Ca2+-handling proteins as well as the impaired interaction of Ca2+ with myofibrils in the aging heart are similar to the alterations that occur in younger individuals with heart failure due to hypertension or myocardial infarction. This chapter addresses some of the mechanisms of defects in Ca2+-handling that produce a deregulation of excitation–contraction coupling (ECC), excitation–metabolism coupling (EMC), and excitation–transcription coupling (ETC) in the senescent heart resulting in ventricular arrhythmias, impaired contractile function, and cardiac remodeling in the aging heart. In addition, it is likely that Ca2+-handling abnormalities are attributable to oxidative stress and changes in membrane compositions due to the aging process. Accordingly, it is suggested that some of the interventions which reduce oxidative stress and slow the progression of aging-induced defects in Ca2+-handling improve function of the aging heart.

Keywords

Sarcoplasmic Reticulum Diastolic Dysfunction Aging Heart Handling Protein Increase Reactive Oxygen Species Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The research in this article was supported by a grant from the Canadian Institute of Health Research (CIHR) and Slovak Scientific Grant Agency (VEGA) 1/0638/12. The infrastructural support for this study was provided by the St. Boniface Hospital Research Foundation. Dr. N.S. Neki was a Visiting Professor from the Government Medical College, Amritsar, India.

References

  1. 1.
    Verbrugge LM, Jette AM. The disablement process. Soc Sci Med. 1994;38:1–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Schwartz JB, Zipes DP. Cardiovascular disease in the elderly. In: Braunwald E, Zipes DP, Libby P, editors. Heart disease. 8th ed. Philadelphia: WB Saunders; 2008. p. 1923–53.Google Scholar
  3. 3.
    Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev. 1993;73:413–67.PubMedGoogle Scholar
  4. 4.
    Lakatta EG, Sollott SJ. Perspectives on mammalian cardiovascular aging: humans to molecules. Comp Biochem Physiol A Mol Integr Physiol. 2002;132:699–721.PubMedCrossRefGoogle Scholar
  5. 5.
    Mehta RH, Rathore SS, Radford MJ, et al. Acute myocardial infarction in the elderly: differences by age. J Am Coll Cardiol. 2001;38:736–41.PubMedCrossRefGoogle Scholar
  6. 6.
    Alexander KP, Newby LK, Armstrong PW, et al. Acute coronary care in the elderly, part II: ST-segment-elevation myocardial infarction: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation. 2007;115:2570–89.PubMedCrossRefGoogle Scholar
  7. 7.
    Lakatta EG, Schulman S. Age-associated cardiovascular changes are the substrate for poor prognosis with myocardial infarction. J Am Coll Cardiol. 2004;44:35–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Granger CB, Goldberg RJ, Dabbous O, et al. Global Registry of Acute Coronary Events Investigators. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med. 2003;163:2345–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Rosamond W, Flegal K, Fridat G, et al. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69–171.PubMedCrossRefGoogle Scholar
  10. 10.
    Dai DF, Rabinovitch PS. Cardiac aging in mice and humans: the role of mitochondrial oxidative stress. Trends Cardiovasc Med. 2009;19:213–20.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Klausner SC, Schwartz AB. The aging heart. Clin Geriatr Med. 1985;1:119–41.PubMedGoogle Scholar
  12. 12.
    Roffe C. Ageing of the heart. Br J Biomed Sci. 1998;55:136–48.PubMedGoogle Scholar
  13. 13.
    Dobson Jr JG, Fenton RA, Romano FD. Increased myocardial adenosine production and reduction of beta-adrenergic contractile response in aged hearts. Circ Res. 1990;66:1381–90.PubMedCrossRefGoogle Scholar
  14. 14.
    Liles JT, Ida KK, Joly KM, et al. Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat. Am J Physiol Regul Integr Comp Physiol. 2011;301:R491–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Rueckschloss U, Villmow M, Klöckner U. NADPH oxidase-derived superoxide impairs calcium transients and contraction in aged murine ventricular myocytes. Exp Gerontol. 2010;45:788–96.PubMedCrossRefGoogle Scholar
  16. 16.
    Anversa P, Palackal T, Sonnenblick EH, et al. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res. 1990;67:871–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Capasso JM, Palackal T, Olivetti G, Anversa P. Severe myocardial dysfunction induced by ventricular remodeling in aging rat hearts. Am J Physiol. 1990;259:H1086–96.PubMedGoogle Scholar
  18. 18.
    Lim CC, Liao R, Varma N, Apstein CS. Impaired lusitropy-frequency in the aging mouse: role of Ca2+-handling proteins and effects of isoproterenol. Am J Physiol. 1999;277:H2083–90.PubMedGoogle Scholar
  19. 19.
    Fleg JL, O'Connor F, Gerstenblith G, et al. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol. 1995;78:890–900.PubMedGoogle Scholar
  20. 20.
    Fraticelli A, Josephson R, Danziger R, et al. Morphological and contractile characteristics of rat cardiac myocytes from maturation to senescence. Am J Physiol. 1989;257:H259–65.PubMedGoogle Scholar
  21. 21.
    Shih H, Lee B, Lee RJ, et al. The aging heart and post-infarction left ventricular remodeling. J Am Coll Cardiol. 2011;57:9–17.PubMedCrossRefGoogle Scholar
  22. 22.
    Dhalla NS, Rangi S, Babick AP, et al. Cardiac remodeling and subcellular defects in heart failure due to myocardial infarction and aging. Heart Fail Rev. 2012;17:671–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Alonso MT, Villalobos C, Chamero P, et al. Calcium microdomains in mitochondria and nucleus. Cell Calcium. 2006;40:513–25.PubMedCrossRefGoogle Scholar
  24. 24.
    Dhalla NS, Saini HK, Tappia PS, et al. Potential role and mechanisms of subcellular remodeling in cardiac dysfunction due to ischemic heart disease. J Cardiovasc Med (Hagerstown). 2007;8:238–50.CrossRefGoogle Scholar
  25. 25.
    Dibb KM, Rueckschloss U, Eisner DA, et al. Mechanisms underlying enhanced cardiac excitation contraction coupling observed in the senescent sheep myocardium. J Mol Cell Cardiol. 2004;37:1171–81.PubMedGoogle Scholar
  26. 26.
    Isenberg G, Borschke B, Rueckschloss U. Ca2+ transients of cardiomyocytes from senescent mice peak late and decay slowly. Cell Calcium. 2003;34:271–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Walker KE, Lakatta EG, Houser SR. Age associated changes in membrane currents in rat ventricular myocytes. Cardiovasc Res. 1993;27:1968–77.PubMedCrossRefGoogle Scholar
  28. 28.
    Wei JY, Spurgeon HA, Lakatta EG. Excitation–contraction in rat myocardium: alterations with adult aging. Am J Physiol. 1984;246:H784–91.PubMedGoogle Scholar
  29. 29.
    Grandy SA, Howlett SE. Cardiac excitation–contraction coupling is altered in myocytes from aged male mice but not in cells from aged female mice. Am J Physiol Heart Circ Physiol. 2006;291:H2362–70.PubMedCrossRefGoogle Scholar
  30. 30.
    Howlett SE, Nicholl PA. Density of 1,4-dihydropyridine receptors decreases in the hearts of aging hamsters. J Mol Cell Cardiol. 1992;24:885–94.PubMedCrossRefGoogle Scholar
  31. 31.
    Li Q, Wu S, Li SY, et al. Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage. Am J Physiol Heart Circ Physiol. 2007;292:H1398–403.PubMedCrossRefGoogle Scholar
  32. 32.
    Froehlich JP, Lakatta EG, Beard E, et al. Studies of sarcoplasmic reticulum function and contraction duration in young adult and aged rat myocardium. J Mol Cell Cardiol. 1978;10:427–38.PubMedCrossRefGoogle Scholar
  33. 33.
    Maciel LM, Polikar R, Rohrer D, et al. Age-induced decreases in the messenger RNA coding for the sarcoplasmic reticulum Ca2+-ATPase of the rat heart. Circ Res. 1990;67:230–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Xu A, Narayanan N. Effects of aging on sarcoplasmic reticulum Ca2+-cycling proteins and their phosphorylation in rat myocardium. Am J Physiol. 1998;275:H2087–94.PubMedGoogle Scholar
  35. 35.
    Kaplan P, Jurkovicova D, Babusikova E, et al. Effect of aging on the expression of intracellular Ca2+-transport proteins in a rat heart. Mol Cell Biochem. 2007;301:219–26.PubMedCrossRefGoogle Scholar
  36. 36.
    Schmidt U, del Monte F, Miyamoto MI, et al. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca2+-ATPase. Circulation. 2000;101:790–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Koban MU, Moorman AF, Holtz J, et al. Expressional analysis of the cardiac Na–Ca exchanger in rat development and senescence. Cardiovasc Res. 1998;37:405–23.PubMedCrossRefGoogle Scholar
  38. 38.
    Guo KK, Ren J. Cardiac overexpression of alcohol dehydrogenase (ADH) alleviates aging-associated cardiomyocyte contractile dysfunction: role of intracellular Ca2+-cycling proteins. Aging Cell. 2006;5:259–65.PubMedCrossRefGoogle Scholar
  39. 39.
    Janapati V, Wu A, Davis N, et al. Post-transcriptional regulation of the Na+/Ca2+ exchanger in aging rat heart. Mech Ageing Dev. 1995;84:195–208.PubMedCrossRefGoogle Scholar
  40. 40.
    Mace LC, Palmer BM, Brown DA, et al. Influence of age and run training on cardiac Na+/Ca2+ exchange. J Appl Physiol. 2003;95:1994–2003.PubMedGoogle Scholar
  41. 41.
    Assayag P, CHarlemagne D, Marty I, et al. Effects of sustained low-flow ischemia on myocardial function and calcium-regulating proteins in adult and senescent rat hearts. Cardiovasc Res. 1998;38:169–80.PubMedCrossRefGoogle Scholar
  42. 42.
    Zhu X, Altschafl BA, Hajjar RJ, et al. Altered Ca2+ sparks and gating properties of ryanodine receptors in aging cardiomyocytes. Cell Calcium. 2005;37:583–91.PubMedCrossRefGoogle Scholar
  43. 43.
    Howlett SE, Grandy SA, Ferrier GR. Calcium spark properties in ventricular myocytes are altered in aged mice. Am J Physiol Heart Circ Physiol. 2006;290:H1566–74.PubMedCrossRefGoogle Scholar
  44. 44.
    Khatter JC. Mechanisms of age-related differences in the cardiotoxic action of digitalis. J Cardiovasc Pharmacol. 1985;7:258–61.PubMedCrossRefGoogle Scholar
  45. 45.
    Carré F, Rannou F, Sainte Beuve C, et al. Arrhythmogenicity of the hypertrophied and senescent heart and relationship to membrane proteins involved in the altered calcium handling. Cardiovasc Res. 1993;27:1784–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Ataka K, Chen D, Levitsky S, et al. Effect of aging on intracellular Ca2+, pHi, and contractility during ischemia and reperfusion. Circulation. 1992;86:II371–6.PubMedGoogle Scholar
  47. 47.
    McLennan PL, Abeywardena ML, Charnock JS. The influence of age and dietary fat in an animal model of sudden cardiac death. Aust NZ J Med. 1989;19:1–5.CrossRefGoogle Scholar
  48. 48.
    Corretti MC, Koretsune Y, Kusuoka H, et al. Glycolytic inhibition and calcium overload as consequences of exogenously generated free radicals in rabbit hearts. J Clin Invest. 1991;88:1014–25.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Nohl H, Hegner D. Do mitochondria produce oxygen radicals in vivo? Eur J Biochem. 1978;82:563–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Sawada M, Carlson JC. Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mech Ageing Dev. 1987;41:125–37.PubMedCrossRefGoogle Scholar
  51. 51.
    Tatarková Z, Kuka S, Račay P, et al. Effects of aging on activities of mitochondrial electron transport chain complexes and oxidative damage in rat heart. Physiol Res. 2011;60:281–9.PubMedGoogle Scholar
  52. 52.
    Ren J, Li Q, Wu S, et al. Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction. Mech Ageing Dev. 2007;128:276–85.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Kaplan P, Babusikova E, Lehotsky J, Dobrota D. Free radical-induced protein modification and inhibition of Ca2+-ATPase of cardiac sarcoplasmic reticulum. Mol Cell Biochem. 2003;248:41–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Thomas MM, Vigna C, Betik AC, et al. Cardiac calcium pump inactivation and nitrosylation in senescent rat myocardium are not attenuated by long-term treadmill training. Exp Gerontol. 2011;46:803–10.PubMedCrossRefGoogle Scholar
  55. 55.
    Robinson I, de Serna DG, Gutierrez A, et al. Vitamin E in humans: an explanation of clinical trial failure. Endocr Pract. 2006;12:576–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Abete P, Ferrara N, Cioppa A, et al. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol. 1996;27:1777–86.PubMedCrossRefGoogle Scholar
  57. 57.
    Bartling B, Friedrich I, Silber RE, Simm A. Ischemic preconditioning is not cardioprotective in senescent human myocardium. Ann Thorac Surg. 2003;76:105–11.PubMedCrossRefGoogle Scholar
  58. 58.
    Tate CA, Hyek MF, Taffet GE. Mechanisms for the responses of cardiac muscle to physical activity in old age. Med Sci Sports Exerc. 1994;26:561–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Qiu X, Brown K, Hirschey MD, et al. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12:662–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Pepe S, Tsuchiya N, Lakatta EG, et al. PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. Am J Physiol. 1999;276:H149–58.PubMedGoogle Scholar
  61. 61.
    Shinmura K, Tamaki K, Sano M, Murata M, Yamakawa H, Ishida H, et al. Impact of long-term caloric restriction on cardiac senescence: caloric restriction ameliorates cardiac diastolic dysfunction associated with aging. J Mol Cell Cardiol. 2011;50:117–27.PubMedCrossRefGoogle Scholar
  62. 62.
    Hafner AV, Dai J, Gomes AP, et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging. 2010;2:914–23.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Adriana Adameova
    • 1
  • Nirankar S. Neki
    • 2
  • Paramjit S. Tappia
    • 3
  • Naranjan S. Dhalla
    • 4
  1. 1.Department of Pharmacology and ToxicologyComenius UniversityBratislavaSlovak Republic
  2. 2.Department of Internal MedicineGovernment Medical College and Guru Nanak Dev HospitalAmritsarIndia
  3. 3.Office of Clinical Research, Asper Clinical Research InstituteSt. Boniface Hospital ResearchWinnipegCanada
  4. 4.Department of PhysiologyFaculty of Medicine, Institute of Cardiovascular Sciences, University of Manitoba, St. Boniface Hospital ResearchWinnipegCanada

Personalised recommendations