Aging and Remodeling of the RAS and RAAS and Related Pathways: Implications for Heart Failure Therapy

  • Bodh I. JugduttEmail author


The aging population and healthcare costs for heart failure (HF) therapy in the elderly (age ≥65 years) are increasing worldwide. Cardiovascular (CV) diseases, including myocardial infarction (MI), hypertension (HTN), and HF, are all more prevalent in the elderly. While the renin–angiotensin system (RAS) has critical functions in CV physiology, an upregulated RAS plays a critical role in CV pathophysiology, including post-MI dilative remodeling and HF associated with low ejection fraction, and in hypertrophic remodeling and fibrosis associated with HTN and HF with preserved ejection fraction. Accordingly, components of the RAS are important targets for CV disease and HF pharmacotherapy. Angiotensin II (AngII) is the primary effector molecule of the RAS, and RAS/AngII inhibitors form the basis of therapy for both elderly and non-elderly HF patients. However, clinical studies indicate that elderly post-MI patients are at higher risk for adverse events despite therapy with RAS/AngII inhibitors. Remodeling of the RAS with aging may account for the poor outcome in the elderly. Aging is associated with increased AngII and other components of the RAS. Enhanced upregulation and/or dysregulation of the RAS and renin–angiotensin–aldosterone system (RAAS) pathways with aging may play a critical role in the accelerated march to HF and the increasing HF burden despite conventional therapy in the elderly. Increased AngII may also explain increased cytosolic and mitochondrial oxidant production, mitochondrial dysfunction, and increased extracellular matrix deposition associated with aging. Disruption of the AngII type 1 receptor confers protection from CV morbidity and mortality and promotes longevity in animal models. More research into the biology of aging-related remodeling of the RAS/RAAS and related pathways (such as kinins, ACE2/Ang (1–7) , and mineralocorticoids) may lead to discovery and development of improved therapies for post-MI and post-HTN cardiac remodeling and HF in the elderly.


Mineralocorticoid Receptor Leave Ventricular Remodel Secretory Leukocyte Protease Inhibitor Adverse Leave Ventricular Remodel Mineralocorticoid Receptor Activation 
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.



This work was supported in part by grant # IAP99003 from the Canadian Institutes of Health Research, Ottawa, Ontario. I am indebted to Catherine Jugdutt for expert assistance.


  1. 1.
    Jugdutt BI. Prevention of heart failure in the elderly: when, where and how to begin. Heart Fail Rev. 2012;15:531–44.Google Scholar
  2. 2.
    Weisfeldt ML. Left ventricular function. In: Weisfeldt ML, editor. The aging heart: its function and response to stress. New York: Raven; 1980. p. 297–316.Google Scholar
  3. 3.
    Lakatta EG, Gerstenblith G, Weisfeldt ML. The aging heart: structure, function, and disease. In: Braunwald E, editor. Heart disease. Philadelphia, PA: Saunders; 1997. p. 1687–700.Google Scholar
  4. 4.
    Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. Part I. Aging arteries: a “set up” for vascular disease. Circulation. 2003;107:139–46.PubMedGoogle Scholar
  5. 5.
    Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. Part II. Circulation. 2003;107:346–54.PubMedGoogle Scholar
  6. 6.
    Jugdutt BI. Aging and remodeling during healing of the wounded heart: current therapies and novel drug targets. Curr Drug Targets. 2008;9:325–44.PubMedGoogle Scholar
  7. 7.
    Bujak M, Kweon HJ, Chatila K, et al. Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J Am Coll Cardiol. 2008;51:1384–92.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Jugdutt BI, Jelani A. Aging and defective healing, adverse remodeling and blunted postconditioning in the reperfused wounded heart. J Am Coll Cardiol. 2008;51:1399–403.PubMedGoogle Scholar
  9. 9.
    Jugdutt BI, Jelani A, Palaniyappan A, et al. Aging-related early changes in markers of ventricular and matrix remodeling after reperfused ST-segment elevation myocardial infarction in the canine model. Effect of early therapy with an angiotensin II type 1 receptor blocker. Circulation. 2010;122:341–51.PubMedGoogle Scholar
  10. 10.
    Jelani A, Jugdutt BI. STEMI and heart failure in the elderly: role of adverse remodeling. Heart Fail Rev. 2010;15:513–21.PubMedGoogle Scholar
  11. 11.
    Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics – 2010 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2010;121:e46–215.PubMedGoogle Scholar
  12. 12.
    Centers for Disease Control and Prevention. Public health and aging: trends in aging: United States and worldwide. MMRW Morb Mortal Wkly Rep. 2003;52:101–6. Accessed 18 Aug 2011.
  13. 13.
    World Health Organization (WHO). Definition of an older or elderly person. Accessed 30 Dec 2009.
  14. 14.
    Jugdutt BI. Aging and heart failure: changing demographics and implications for therapy in the elderly. Heart Fail Rev. 2010;15:401–5.PubMedGoogle Scholar
  15. 15.
    Roebuck J. When does old age begin? The evolution of the English definition. J Soc Hist. 1979;12:416–28.Google Scholar
  16. 16.
    Holborn, H. A history of modern Germany – 1840–1945. Princeton University Press; 1969. p. 291–3.Google Scholar
  17. 17.
    Jugdutt BI. Heart failure in the elderly: advances and challenges. Expert Rev Cardiovasc Ther. 2010;8:695–715.PubMedGoogle Scholar
  18. 18.
    Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to update the 2001 guidelines for the evaluation and management of heart failure. Circulation. 2005;112:e154–235.PubMedGoogle Scholar
  19. 19.
    Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119:1977–2016.PubMedGoogle Scholar
  20. 20.
    Johansen H, Strauss B, Arnold MO, Moe G, Liu P. On the rise: the current and projected future burden of congestive heart failure hospitalization in Canada. Can J Cardiol. 2003;19:430–5.PubMedGoogle Scholar
  21. 21.
    Arnold MO, Liu P, Demers C, et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and treatment. Can J Cardiol. 2006;22:23–45.PubMedGoogle Scholar
  22. 22.
    Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the task force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Eur J Heart Fail. 2008;10:933–89.PubMedGoogle Scholar
  23. 23.
    McMurray J, Adamopoulos S, Anker S, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 – the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14:803–69.PubMedGoogle Scholar
  24. 24.
    Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly. J Am Coll Cardiol. 2011;57:2037–114.PubMedGoogle Scholar
  25. 25.
    Jugdutt BI. Optimal medical therapy for optimal healing. In: Lewis BS, Flugelman MY, Halon DA, editors. Proceedings 9th International Congress on Coronary Artery disease. Coronary artery diseases 2011 update– from Prevention to Intervention, Venice 2011. Bologna, Italy: Medimond; 2011. p. 243–7.Google Scholar
  26. 26.
    Jugdutt BI, Jelani A. Aging and markers of adverse remodeling after myocardial infarction. In: Jugdutt BI, Dhalla NS, editors. Cardiac remodeling. Molecular mechanisms. New York: Springer; 2013. p. 487–512.Google Scholar
  27. 27.
    Jugdutt BI. Aging and remodeling of the renin-angiotensin-system post infarction. In: Kimchi A, editor. Proceedings 15th World congress on Heart Disease, Vancouver 2010. Bologna, Italy: Medimond; 2010. p. 87–91.Google Scholar
  28. 28.
    Alexander KP, Newby LK, Armstrong PW, et al. American Heart Association Council on Clinical Cardiology; Society of Geriatric Cardiology. 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 for Clinical Cardiology. Circulation. 2007;115:2570–89.PubMedGoogle Scholar
  29. 29.
    Jugdutt BI. Valsartan in the treatment of heart attack survivors. Vasc Health Risk Manag. 2006;2:125–38.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Heymes C, Silvestre JS, Llorens-Cortes C, et al. Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Endocrinology. 1998;139:2579–87.PubMedGoogle Scholar
  31. 31.
    Cao XJ, Li YF. Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats. Can J Cardiol. 2009;25:415–20.PubMedGoogle Scholar
  32. 32.
    De Cavanagh EM, Ferder M, Inserra F, Ferder L. Angiotensin II, mitochondria, cytoskeletal, and extracellular matrix connections: an integrating viewpoint. Am J Physiol Heart Circ Physiol. 2009;296:H550–8.PubMedGoogle Scholar
  33. 33.
    Benigni A, Corna D, Zoja C, et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest. 2009;119:524–30.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Fleg JL, Lakatta EG. Normal aging of the cardiovascular system. In: Aronow WS, Fleg JL, Rich MW, editors. Cardiovascular disease in the elderly. 4th ed. New York, NY: Informa; 2008. p. 1–43.Google Scholar
  35. 35.
    McCullough PA, Khandelwal AK, McKinnon JE, et al. Outcomes and prognostic factors of systolic as compared with diastolic heart failure in urban America. Congest Heart Fail. 2005;11:6–11.PubMedGoogle Scholar
  36. 36.
    McDonald K. Diastolic heart failure in the elderly: underlying mechanisms and clinical relevance. Int J Cardiol. 2008;125:197–202.PubMedGoogle Scholar
  37. 37.
    Jugdutt BI. Extracellular matrix and cardiac remodeling. In: Villarreal FJ, editor. Interstitial fibrosis in heart failure. New York, NY: Springer; 2004. p. 23–55.Google Scholar
  38. 38.
    Jugdutt BI. Regulation of fibrosis after myocardial infarction: implications for ventricular remodeling. In: Jugdutt BI, Dhalla NS, editors. Cardiac remodeling. Molecular mechanisms. New York, NY: Springer; 2013. p. 525–45.Google Scholar
  39. 39.
    Jugdutt BI. Angiotensin II, receptor blockers. In: Crawford MH, editor. Cardiology clinics annual of drug therapy, vol. 2. Philadelphia, PA: W.B. Saunders; 1998. p. 1–17.Google Scholar
  40. 40.
    Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med. 1993;153:937–42.PubMedGoogle Scholar
  41. 41.
    Dzau VJ. Theodore Cooper lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension. 2001;37:1047–52.PubMedGoogle Scholar
  42. 42.
    Kumar R, Thomas CM, Yong QC, Chen W, Baker KM. The intracrine renin-angiotensin system. Clin Sci (Lond). 2012;123:273–84.Google Scholar
  43. 43.
    de Gasparo M, Levens N. Does blockade of angiotensin II receptors offer clinical benefits over inhibition of angiotensin-converting enzyme? Pharmacol Toxicol. 1998;82:257–71.PubMedGoogle Scholar
  44. 44.
    Opie LH, Sack MN. Enhanced angiotensin II activity in heart failure: reevaluation of the counterregulatory hypothesis of receptor subtypes. Circ Res. 2001;88:654–8.PubMedGoogle Scholar
  45. 45.
    Drexler H. Endothelial dysfunction in heart failure and potential for reversal by ACE inhibition. Br Heart J. 1994;72(3 Suppl):S11–4.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Seyedi N, Xu X, Nasjletti A, et al. Coronary kinin generation mediates nitric oxide release after angiotensin receptor stimulation. Hypertension. 1995;26:164–70.PubMedGoogle Scholar
  47. 47.
    Liu YH, Yang XP, Sharov VG, et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997;99:1926–35.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Liu YH, Yang XP, Shesely EG, Sankey SS, Carretero OA. Role of angiotensin II type 2 receptors and kinins in the cardioprotective effect of angiotensin II type 1 receptor antagonists in rats with heart failure. J Am Coll Cardiol. 2004;43:1473–80.PubMedGoogle Scholar
  49. 49.
    Messadi-Laribi E, Griol-Charhbill V, Pizard A, et al. Tissue kallikrein is involved in the cardioprotective effect of AT1-receptor blockade in acute myocardial ischemia. J Pharmacol Exp Ther. 2007;323:210–6.PubMedGoogle Scholar
  50. 50.
    Xu Y, Menon V, Jugdutt BI. Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-epsilon in acutely reperfused myocardial infarction in the dog. Effect of UP269-6 and losartan on AT1 and AT2-receptor expression and IP3 receptor and PKCε proteins. J Renin Angiotensin Aldosterone Syst. 2000;1:184–95.PubMedGoogle Scholar
  51. 51.
    Jugdutt BI, Balghith M. Enhanced regional AT2-receptor and PKCε expression during cardioprotection induced by AT1-receptor blockade after reperfused myocardial infarction. J Renin Angiotensin Aldosterone Syst. 2001;2:134–40.PubMedGoogle Scholar
  52. 52.
    Jugdutt BI, Menon V. AT1 receptor blockade limits myocardial injury and upregulates AT2 receptors during reperfused myocardial infarction. Mol Cell Biochem. 2004;260:111–8.PubMedGoogle Scholar
  53. 53.
    Jugdutt BI, Menon V. Valsartan-induced cardioprotection involves angiotensin II type 2 receptor upregulation in dog and rat in vivo models of reperfused myocardial infarction. J Cardiac Fail. 2004;10:74–82.Google Scholar
  54. 54.
    Rhaleb N-E, Yang X-P, Carretero OA. The kallikrein‐kinin system as a regulator of cardiovascular and renal function. Compr Physiol. 2011;1:971–93.PubMedGoogle Scholar
  55. 55.
    Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem. 1990;265:22348–57.PubMedGoogle Scholar
  56. 56.
    Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res. 1990;66:883–90.PubMedGoogle Scholar
  57. 57.
    Kawamura M, Imanashi M, Matsushima Y, et al. Circulating angiotensin II levels under repeated administration of lisinopril in normal subjects. Clin Exp Pharmacol Physiol. 1992;19:547–53.PubMedGoogle Scholar
  58. 58.
    Jorde UP, Ennezat PV, Lisker J, et al. Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation. 2000;101:844–6.PubMedGoogle Scholar
  59. 59.
    Wolny A, Clozel JP, Rein J, et al. Functional and biochemical analysis of angiotensin II-forming pathways in the human heart. Circ Res. 1997;80:219–27.PubMedGoogle Scholar
  60. 60.
    Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation. 2004;109:2492–9.PubMedGoogle Scholar
  61. 61.
    Spinale FG, de Gasparo M, Whitebread S, et al. Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: I. Effects on left ventricular performance and neurohormonal systems. Circulation. 1997;96:2385–96.PubMedGoogle Scholar
  62. 62.
    Hamroff G, Katz SD, Mancini D, et al. Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure. Circulation. 1999;99:990–2.PubMedGoogle Scholar
  63. 63.
    Yu CM, Tipoe GL, Wing-Hon Lai K, et al. Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction. J Am Coll Cardiol. 2001;38:1207–15.PubMedGoogle Scholar
  64. 64.
    Forteza R, Lauredo I, Abraham WM, Conner GE. Bronchial tissue kallikrein activity is regulated by hyaluronic acid binding. Am J Respir Cell Mol Biol. 1999;21:666–74.PubMedGoogle Scholar
  65. 65.
    Hara M, Ono K, Hwang MW, et al. Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med. 2002;195:375–81.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Matsumoto T, Wada A, Tsutamoto T, et al. Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. Circulation. 2003;107:2555–8.PubMedGoogle Scholar
  67. 67.
    Jin D, Takai S, Sakaguchi M, Okamoto Y, Muramatsu M, Miyazaki M. An antiarrhythmic effect of a chymase inhibitor after myocardial infarction. J Pharmacol Exp Ther. 2004;309:490–7.PubMedGoogle Scholar
  68. 68.
    Jin D, Takai S, Yamada M, et al. Impact of chymase inhibitor on cardiac function and survival after myocardial infarction. Cardiovasc Res. 2003;60:413–20.PubMedGoogle Scholar
  69. 69.
    Matsumoto C, Hayashi T, Kitada K, et al. Chymase plays an important role in left ventricular remodeling influenced by intermittent hypoxia in mice. Hypertension. 2009;54:164–71.PubMedGoogle Scholar
  70. 70.
    Oyamada S, Bianchi C, Takai S, Chu LM, Selke FW. Chymase inhibition reduces infarction and matrix metalloproteinase-9 activation and attenuates inflammation and fibrosis after acute myocardial ischemia/reperfusion. J Pharmacol Exp Ther. 2011;339:143–51.PubMedGoogle Scholar
  71. 71.
    Wei CC, Hase N, Inoue Y, et al. Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents. J Clin Invest. 2010;120:1229–39.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Pat B, Chen Y, Killingsworth C, Gladden JD, et al. Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation. Circulation. 2011;122:1488–95.Google Scholar
  73. 73.
    Okumura K, Takai S, Muramatsu M, et al. Human chymase degrades human fibronectin. Clin Chim Acta. 2004;347:223–5.PubMedGoogle Scholar
  74. 74.
    Hoshino F, Urata H, Inoue Y, et al. Chymase inhibitor improves survival in hamsters with myocardial infarction. J Cardiovasc Pharmacol. 2003;41 Suppl 1:S11–8.PubMedGoogle Scholar
  75. 75.
    Ihara M, Urata H, Shirai K, et al. High cardiac angiotensin-II-forming activity in infarcted and non-infarcted human myocardium. Cardiology. 2000;94:247–53.PubMedGoogle Scholar
  76. 76.
    Ihara M, Urata H, Kinoshita A, et al. Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension. 1999;33:1399–405.PubMedGoogle Scholar
  77. 77.
    Arakawa K, Urata H. Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension. 2000;36:638–41.PubMedGoogle Scholar
  78. 78.
    Uehara Y, Urata H, Sasaguri M, et al. Increased chymase activity in internal thoracic artery of patients with hypercholesterolemia. Hypertension. 2000;35:55–60.PubMedGoogle Scholar
  79. 79.
    Uehara Y, Urata H, Ideishi M, Arakawa K, Saku K. Chymase inhibition suppresses high-cholesterol diet-induced lipid accumulation in the hamster aorta. Cardiovasc Res. 2002;55:870–6.PubMedGoogle Scholar
  80. 80.
    Koka V, Wang W, Huang XR, et al. Advanced glycation end products activate a chymase-dependent angiotensin II-generating pathway in diabetic complications. Circulation. 2006;113:1353–60.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Singh VP, Baker KM, Kumar R. Activation of the intracellular renin angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol. 2008;294:H1675–84.Google Scholar
  82. 82.
    New RB, Sampson AC, King MK, et al. Effects of combined angiotensin II and endothelin receptor blockade with developing heart failure: effects on left ventricular performance. Circulation. 2000;102:1447–53.PubMedGoogle Scholar
  83. 83.
    Rossi GP, Sacchetto A, Cesari M, Pessina AC. Interactions between endothelin-1 and the renin-angiotensin-aldosterone system. Cardiovasc Res. 1999;43:300–7.PubMedGoogle Scholar
  84. 84.
    Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation. 2000;102:2434–40.PubMedGoogle Scholar
  85. 85.
    Teerlink JR. Endothelins: pathophysiology and treatment implications in chronic heart failure. Curr Heart Fail Rep. 2005;2:191–7.PubMedGoogle Scholar
  86. 86.
    Schirger JA, Chen HH, Jougasaki M, et al. Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention. Circulation. 2004;109:249–54.PubMedGoogle Scholar
  87. 87.
    Anand I, McMurray J, Cohn JN, et al. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:347–54.PubMedGoogle Scholar
  88. 88.
    Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation. 2000;102:1718–23.PubMedGoogle Scholar
  89. 89.
    Jiang BH, Tardif J-C, Shi Y, Dupuis J. Bosentan does not improve pulmonary hypertension and lung remodeling in heart failure. Eur Respir J. 2011;37:578–86.PubMedGoogle Scholar
  90. 90.
    Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult – a summary statement from the Pulmonary Hypertension Council of the International Society for heart and Lung Transplantation. J Heart Lung Transplant. 2012;31:913–33.PubMedGoogle Scholar
  91. 91.
    Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275:33238–43.PubMedGoogle Scholar
  92. 92.
    Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87:E1–9.PubMedGoogle Scholar
  93. 93.
    Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 as an essential regulator of heart function. Nature. 2002;417:822–8.PubMedGoogle Scholar
  94. 94.
    Ferrario CM, Trask AJ, Jessup JA. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol. 2005;289:H2281–90.Google Scholar
  95. 95.
    Iwata M, Cowling RT, Gurantz D, et al. Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects. Am J Physiol. 2005;289:H2356–63.Google Scholar
  96. 96.
    Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111:2605–10.PubMedGoogle Scholar
  97. 97.
    Ishiyama Y, Gallagher PE, Averill DB, et al. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43:970–6.PubMedGoogle Scholar
  98. 98.
    Loot AE, Roks AJ, Henning RH, et al. Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation. 2002;105:1548–50.PubMedGoogle Scholar
  99. 99.
    Ocaranza MP, Godoy I, Jalil JE, et al. Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension. 2006;48:572–8.PubMedGoogle Scholar
  100. 100.
    Zhong JC, Ye JY, Jin HY, et al. Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profiling-1 expression. Regul Pept. 2011;166:90–7.PubMedGoogle Scholar
  101. 101.
    Jugdutt B, Palaniyappan A, Idikio H. Role of ACE2 and Ang (1-7) in limiting fibrosis and remodeling during healing after reperfused myocardial infarction. J Mol Cell Cardiol. 2009;57:S24 (Abstract).Google Scholar
  102. 102.
    Cowling RT, Goldberg BH. The ACE2/Ang-(1-7) pathway in cardiac fibroblasts as a potential target for cardiac remodeling. In: Jugdutt BI, Dhalla NS, editors. Cardiac remodeling. Molecular mechanisms. New York, NY: Springer; 2013. p. 547–57.Google Scholar
  103. 103.
    Wang W, Bodiga S, Das SK, et al. Role of ACE2 in diastolic and systolic heart failure. Heart Fail Rev. 2012;17:683–9.PubMedGoogle Scholar
  104. 104.
    Zisman LS, Keller RS, Weaver B, et al. Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2. Circulation. 2003;108:1707–12.PubMedGoogle Scholar
  105. 105.
    Zhao YX, Yin HQ, Yu QT, et al. ACE2 overexpression ameliorates left ventricular remodeling and dysfunction in a rat model of myocardial infarction. Hum Gene Ther. 2010;21:1545–54.PubMedGoogle Scholar
  106. 106.
    Epelman S, Shrestha K, Troughton RW, et al. Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes. J Card Fail. 2009;15:565–71.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Wang Y, Moreira Mda C, Heringer-Walther S, et al. Plasma ACE2 activity is an independent prognostic marker in Chagas’ disease and equally potent as BNP. J Card Fail. 2010;16:157–63.PubMedGoogle Scholar
  108. 108.
    Xie X, Chen J, Wang X, et al. Age- and gender-related difference of ACE2 expression in a rat lung. Life Sci. 2006;78:2166–71.PubMedGoogle Scholar
  109. 109.
    Yousif MH, Kehinde EO, Benter IF. Different responses to angiotensin-(1-7) in young, aged and diabetic rabbit corpus cavernosum. Pharmacol Res. 2007;56:209–16.PubMedGoogle Scholar
  110. 110.
    Palaniyappan A, Idikio H, Jugdutt BI. Effect of age on expression of AT1 and AT2 receptors and ACE-2 and Angiotensin (1-7), Ac-SDKP and Smad-2 proteins after acute reperfused ST-segment myocardial infarction. Circulation. 2008;118 Suppl 2:S547 (Abstract).Google Scholar
  111. 111.
    Tom B, de Vries R, Saxena PR, et al. Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade. Hypertension. 2001;38:95–9.PubMedGoogle Scholar
  112. 112.
    Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation. 2005;111:315–20.PubMedGoogle Scholar
  113. 113.
    Nagata S, Kato J, Sasaki K, et al. Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system. Biochem Biophys Res Commun. 2006;350:1026–31.PubMedGoogle Scholar
  114. 114.
    Jessup JA, Trask AJ, Chappell MC, et al. Localization of the novel angiotensin peptide, angiotensin-(1-12), in heart and kidney of hypertensive and normotensive rats. Am J Physiol. 2008;294:H2614–8.Google Scholar
  115. 115.
    Trask AJ, Jessup JA, Chappell MC, Ferrario CM. Angiotensin-(1-12) is an alternate substrate for angiotensin peptide production in the heart. Am J Physiol. 2008;294:H2242–7.Google Scholar
  116. 116.
    Ferrario C, Varagic J, Hanini J, et al. Differential regulation of angiotensin-(1-12) in plasma and cardiac tissue in response to bilateral nephrectomy. Am J Physiol. 2009;296:H1184–92.Google Scholar
  117. 117.
    Prosser HC, Forster ME, Richards AM, Pemberton CJ. Cardiac chymase converts rat proAngiotensin-12 (PA12) to angiotensin II: effects of PA12 upon cardiac haemodynamics. Cardiovasc Res. 2009;82:40–50.PubMedGoogle Scholar
  118. 118.
    Ahmad S, Simmons T, Varagic J, et al. Chymase-dependent generation of angiotensin II from angiotensin-(1-12) in human atrial tissue. PLoS One. 2011;6:e28501.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Ahmad S, Wei CC, Tallaj J, et al. Chymase mediates angiotensin-(1-12) metabolism in human hearts. J Am Soc Hypertens. 2013;7:128–36.PubMedGoogle Scholar
  120. 120.
    Moniwa N, Wei C-C, dell’Italia LJ, et al. Chymase-mediated angiotensin II generation from angiotensin-(1-12) in left ventricular tissue of normal and diseased human subjects. J Clin Hypertens (Greenwich). 2012;14 Suppl 1:149 (Abstract).Google Scholar
  121. 121.
    The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–35.Google Scholar
  122. 122.
    Giles TD, Katz R, Sullivan JM, et al. Short- and long-acting angiotensin-converting enzyme inhibitors: a randomized trial of lisinopril versus captopril in the treatment of congestive heart failure. The Multicenter Lisinopril-Captopril Congestive Heart Failure Study Group. J Am Coll Cardiol. 1989;13:1240–7.PubMedGoogle Scholar
  123. 123.
    The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.Google Scholar
  124. 124.
    The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–91.Google Scholar
  125. 125.
    Ryden L, Armstrong PW, Cleland JG, et al. Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial. Eur Heart J. 2000;21:1967–78.PubMedGoogle Scholar
  126. 126.
    Cleland JG, Tendera M, Adamus J, The PEPCHF Investigators, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338–45.PubMedGoogle Scholar
  127. 127.
    Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349:747–52.PubMedGoogle Scholar
  128. 128.
    McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation. 1999;100:1056–64.PubMedGoogle Scholar
  129. 129.
    Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial−the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582–7.PubMedGoogle Scholar
  130. 130.
    Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–75.PubMedGoogle Scholar
  131. 131.
    Pfeffer MA, Swedberg K, Granger CB, et al. CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759–66.PubMedGoogle Scholar
  132. 132.
    McMurray JJ, Ostergren J, Swedberg K, et al. CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767–71.PubMedGoogle Scholar
  133. 133.
    Granger CB, McMurray JJ, Yusuf S, et al. CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772–6.PubMedGoogle Scholar
  134. 134.
    Yusuf S, Pfeffer MA, Swedberg K, et al. CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet. 2003;362:777–81.PubMedGoogle Scholar
  135. 135.
    White HD, Aylward PE, Huang Z, et al. Mortality and morbidity remain high despite captopril and/or valsartan therapy in elderly patients with left ventricular systolic dysfunction, heart failure, or both after acute myocardial infarction: results of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Circulation. 2005;112:3391–9.PubMedGoogle Scholar
  136. 136.
    Massie BM, Carson PE, McMurray JJ, et al. I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456–67.PubMedGoogle Scholar
  137. 137.
    Timmermans PB, Carini DJ, Chiu AT, et al. The discovery of a new class of highly specific nonpeptide angiotensin II receptor antagonists. Am J Hypertens. 1991;4:275S–81.PubMedGoogle Scholar
  138. 138.
    Buhler FR, Laragh JH, Baer L, et al. Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. N Engl J Med. 1972;287:1209–14.PubMedGoogle Scholar
  139. 139.
    Campbell DJ, Aggarwal A, Esler M, et al. β-blockers, angiotensin II, and ACE inhibitors in patients with heart failure. Lancet. 2001;358:1609–10.PubMedGoogle Scholar
  140. 140.
    Sharpe N. Benefit of beta-blockers for heart failure: proven in 1999. Lancet. 1999;353:1988–9.PubMedGoogle Scholar
  141. 141.
    Benz J, Oshrain C, Henry D, et al. Valsartan, a new angiotensin II receptor antagonist: a double-blind study comparing the incidence of cough with lisinopril and hydrochlorothiazide. J Clin Pharmacol. 1997;37:101–7.PubMedGoogle Scholar
  142. 142.
    Howes LG, Tran D. Can angiotensin receptor antagonists be used safely in patients with previous ACE inhibitor-induced angioedema? Drug Saf. 2002;25:73–6.PubMedGoogle Scholar
  143. 143.
    Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–906.PubMedGoogle Scholar
  144. 144.
    Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42:1206–52.PubMedGoogle Scholar
  145. 145.
    Chobanian AV, Bakris GL, Black HR, et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289:2560–72.PubMedGoogle Scholar
  146. 146.
    Rosendorff C, Black HR, Cannon CP, et al. American Heart Association Council for High Blood Pressure Research; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Epidemiology and Prevention. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation. 2007;115:2761–88.PubMedGoogle Scholar
  147. 147.
    Mancia G, De Backer G, Dominiczak A, et al. Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007;28:1462–536.PubMedGoogle Scholar
  148. 148.
    Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327:669–77.PubMedGoogle Scholar
  149. 149.
    Fox KM, The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782–8.PubMedGoogle Scholar
  150. 150.
    Pitt B, O’Neill B, Feldman R, et al. QUIET Study Group. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:1058–63.PubMedGoogle Scholar
  151. 151.
    Braunwald E, Domanski MJ, Fowler SE, et al. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2003;362:782–8.Google Scholar
  152. 152.
    Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet. 2006;368:581–8.PubMedGoogle Scholar
  153. 153.
    Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–9.Google Scholar
  154. 154.
    Yusuf S, Sleight P, Pogue J, et al. HOPE/HOPE-TOO Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–53.PubMedGoogle Scholar
  155. 155.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456–62.PubMedGoogle Scholar
  156. 156.
    Bosch J, Lonn E, Pogue J, et al. HOPE/HOPE_TOO Study Investigators. Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension. Circulation. 2005;112:1339–46.PubMedGoogle Scholar
  157. 157.
    Patel A, MacMahon S, Chalmers J, et al. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829–40.PubMedGoogle Scholar
  158. 158.
    Kjeldsen SE, Lyle PA, Tershakovec AM, et al. Targeting the renin-angiotensin system for the reduction of cardiovascular outcomes in hypertension: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Expert Opin Emerg Drugs. 2005;10:729–45.PubMedGoogle Scholar
  159. 159.
    Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation. 2006;114:838–54.PubMedGoogle Scholar
  160. 160.
    Tikkanen I, Omvik P, Jensen HA. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension. J Hypertens. 1995;13:1343–51.PubMedGoogle Scholar
  161. 161.
    Holwerda NJ, Fogari R, Angeli P, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy and safety compared with placebo and enalapril. J Hypertens. 1996;14:1147–51.PubMedGoogle Scholar
  162. 162.
    Chan P, Tomlinson B, Huang TY, et al. Double-blind comparison of losartan, lisinopril, and metolazone in elderly hypertensive patients with previous angiotensin-converting enzyme inhibitor-induced cough. J Clin Pharmacol. 1997;37:253–7.PubMedGoogle Scholar
  163. 163.
    Dahlof B, Devereux RB, Kjeldsen SE, et al. LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003.PubMedGoogle Scholar
  164. 164.
    Dickstein K, Kjekshus J, OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet. 2002;360:752–60.PubMedGoogle Scholar
  165. 165.
    Volpe M, Mancia G, Trimarco B. Angiotensin II receptor blockers and myocardial infarction: deeds and misdeeds. J Hypertens. 2005;23:2113–8.PubMedGoogle Scholar
  166. 166.
    Yusuf S, Teo KK, Pogue J, et al. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547–59.PubMedGoogle Scholar
  167. 167.
    Yusuf S, Diener HC, Sacco RL, et al. PROFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359:1225–37.PubMedCentralPubMedGoogle Scholar
  168. 168.
    Yusuf S, Teo K, Anderson C, et al. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174–83.PubMedGoogle Scholar
  169. 169.
    Verdecchia P, Sleight P, Mancia G, et al. ONTARGET/TRANSCEND Investigators. Effects of telmisartan, ramipril, and their combination on left ventricular hypertrophy in individuals at high vascular risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End point Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease. Circulation. 2009;120:1380–9.PubMedGoogle Scholar
  170. 170.
    Shivakumar K, Dostal DE, Boheler K, et al. Differential response of cardiac fibroblasts from young and senescent rats to ANG II. Am J Physiol Heart Circ Physiol. 2003;284:H1454–9.PubMedGoogle Scholar
  171. 171.
    Basso N, Cini R, Pietrelli A, et al. Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol. 2007;293:H1351–8.PubMedGoogle Scholar
  172. 172.
    Lewis EF, Moye LA, Rouleau JL, et al. Predictors of late development of heart failure in stable survivors of myocardial infarction: the CARE study. J Am Coll Cardiol. 2003;42:1446–53.PubMedGoogle Scholar
  173. 173.
    St John Sutton M, Pfeffer MA, Moye L, et al. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation. 1997;96:3294–9.PubMedGoogle Scholar
  174. 174.
    Maggioni AP, Maseri A, Fresco C, et al. Age-related increase in mortality among patients with first myocardial infarctions treated with thrombolysis. The investigators of the gruppo Italiano per lo Studio della supravvivenza nell’Infarcto Miocardico (GISSI-2). N Engl J Med. 1993;329:1442–8.PubMedGoogle Scholar
  175. 175.
    Jugdutt BI. Prevention of ventricular remodeling after myocardial infarction and in congestive heart failure. Heart Fail Rev. 1996;1:115–29.Google Scholar
  176. 176.
    Jugdutt BI. Ventricular remodeling post-infarction and the extracellular collagen matrix. When is enough enough? Circulation. 2003;108:1395–403.PubMedGoogle Scholar
  177. 177.
    Jugdutt BI. Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Curr Drug Targets Cardiovasc Haematol Disord. 2003;3:1–30.PubMedGoogle Scholar
  178. 178.
    Kim CB, Braunwald E. Potential benefits of late reperfusion of infarcted myocardium. The open artery hypothesis. Circulation. 1993;88:2426–36.PubMedGoogle Scholar
  179. 179.
    Bolognese L, Neskovic AN, Parodi G, et al. Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation. 2002;106:2351–7.PubMedGoogle Scholar
  180. 180.
    Bolognese L, Carrabba N, Parodi G, et al. Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after primary coronary angioplasty for acute myocardial infarction. Circulation. 2004;109:1121–6.PubMedGoogle Scholar
  181. 181.
    Ferrari R, for the PREAMI Investigators. Effects of angiotensin-converting enzyme inhibition with peridopril on left ventricular remodeling and clinical outcome. Results of the randomized Perindopril and Remodeling Elderly with Acute Myocardial Infarction (PREAMI) study. Arch Intern Med. 2006;166:659–66.PubMedGoogle Scholar
  182. 182.
    Jugdutt BI, Palaniyappan A, Uwiera RRE, Idikio H. Role of healing-specific-matricellular proteins and matrix metalloproteinases in age-related enhanced early remodeling after reperfused STEMI in dogs. Mol Cell Biochem. 2009;322:25–36.PubMedGoogle Scholar
  183. 183.
    Palaniyappan A, Idikio H, Jugdutt BI. Secretory leucocyte protease inhibitor and matricellular protein modulation of post reperfused myocardial infarction healing, fibrosis and remodeling in rat model. Effect of candesartan and omapatrilat. Circulation. 2009;120 Suppl 2:S837 (Abstract).Google Scholar
  184. 184.
    Carey RM. Angiotensin receptors and aging. Hypertension. 2007;50:33–4.PubMedGoogle Scholar
  185. 185.
    Pinaud F, Bocquet A, Dumont O, et al. Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats. Hypertension. 2007;50:96–102.PubMedCentralPubMedGoogle Scholar
  186. 186.
    Savoia C, Touyz RM, Volpe M, Schiffrin EL. Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients. Hypertension. 2007;49:341–6.PubMedGoogle Scholar
  187. 187.
    Chen W, Frangogiannis NG. The role of inflammatory and fibrogenic pathways in heart failure associated with aging. Heart Fail Rev. 2010;15:415–22.PubMedCentralPubMedGoogle Scholar
  188. 188.
    Ho D, Yan L, Iwatsubo K, Vatner DE, Varner SF. Modulation of β-adrenergic receptor signaling in heart failure and longevity: targeting adenyl cyclase type 5. Heart Fail Rev. 2010;15:495–512.PubMedCentralPubMedGoogle Scholar
  189. 189.
    Pitt B. The role of mineralocorticoid receptor antagonists (MRAs) in very old patients with heart failure. Heart Fail Rev. 2012;17:573–9.PubMedGoogle Scholar
  190. 190.
    Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet. 1987;1(8533):581–4.PubMedGoogle Scholar
  191. 191.
    Jugdutt BI. Intravenous nitroglycerin unloading in acute myocardial infarction. Am J Cardiol. 1991;68(14):52D–63.PubMedGoogle Scholar
  192. 192.
    Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ. 2004;329:1248–9.PubMedGoogle Scholar
  193. 193.
    Thomas GN, Chan P, Tomlinson B. The role of angiotensin II type 1 receptor antagonists in elderly patients with hypertension. Drugs Aging. 2006;23:131–55.PubMedGoogle Scholar
  194. 194.
    Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.PubMedGoogle Scholar
  195. 195.
    Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000;102:2700–6.PubMedGoogle Scholar
  196. 196.
    Pitt B, Remme W, Zannad F, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.PubMedGoogle Scholar
  197. 197.
    Pitt B, White H, Nicolau J, et al. EPHESUS Investigators. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. 2005;46:425–31.PubMedGoogle Scholar
  198. 198.
    Mak GJ, Ledwidge MT, Watson CJ, et al. Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone. J Am Coll Cardiol. 2009;54:1674–82.PubMedGoogle Scholar
  199. 199.
    Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.PubMedGoogle Scholar
  200. 200.
    Li X, Qi Y, Li Y, et al. Impact of mineralocorticoid receptor antagonists on changes in cardiac structure and function of left ventricular dysfunction. A meta-analysis of randomized controlled trials. Circ Heart Fail. 2013;6:156–65.PubMedGoogle Scholar
  201. 201.
    Weidmann P, de Myttenaere-Bursztein S, Maxwell MK, de Lima J. Effect of aging on plasma renin and aldosterone in normal man. Kidney Int. 2008;8:325–33.Google Scholar
  202. 202.
    Henschkowski J, Stuck AE, Frey BM, et al. Age-dependent decrease 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) activity in hypertensive patients. Am J Hypertens. 2008;21:644–9.PubMedGoogle Scholar
  203. 203.
    Funder JW, Pearce P, Smith R, Smith AL. Mineralocorticoid action: target–tissue specificity is enzyme, not receptor mediated. Science. 1988;242:583–5.PubMedGoogle Scholar
  204. 204.
    Edwards CR, Stewart PM, Burt D, et al. Localization of 11 beta-hydroxysteroid dehydrogenase-tissue specific receptor of the mineralocorticoid receptor. Lancet. 1988;2:986–9.PubMedGoogle Scholar
  205. 205.
    Funder JW. Rales, ephesus and redox. J Steroid Biochem Mol Biol. 2005;93:121–5.PubMedGoogle Scholar
  206. 206.
    Funder WF. Reconsidering the roles of the mineralocorticoid receptor. Hypertension. 2008;53(Pt 2):286–90.Google Scholar
  207. 207.
    Bocchi B, Kenouch S, Lamarre-Cliche M, et al. Impaired 11-beta hydroxysteroid dehydrogenase type 2 activity in sweat gland ducts in human essential hypertension. Hypertension. 2004;43:803–8.PubMedGoogle Scholar
  208. 208.
    Chai W, Danser AHJ. Why are mineralocorticoid receptor antagonists cardioprotective? Naunyn Schmiedebergs Arch Pharmacol. 2006;374:153–62.PubMedCentralPubMedGoogle Scholar
  209. 209.
    Krug AW, Allenhofer L, Monticone R, et al. Elevated mineralocorticoid receptor activity in aged rat vascular smooth muscle cells promotes a proinflammatory phenotype via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and epidermal growth factor receptor-dependent pathways. Hypertension. 2010;55:1476–83.PubMedCentralPubMedGoogle Scholar
  210. 210.
    Vasan RS, Demisse S, Kimura M, et al. Association of leucocyte telomere length with circulating biomarkers of the renin-angiotensin-aldosterone system: the Framingham Heart Study. Circulation. 2008;117:1138–44.PubMedCentralPubMedGoogle Scholar
  211. 211.
    Benetos A, Gardner JP, Kimura M, et al. Aldosterone and telomere length in white blood cells. J Gerontol A Biol Sci Med Sci. 2005;60:1593–6.PubMedGoogle Scholar
  212. 212.
    Pitt B, Reichek N, Willenbrock R, et al. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation. 2003;108:1831–8.PubMedGoogle Scholar
  213. 213.
    Mottram PM, Haluska B, Leano R, et al. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004;110:558–65.PubMedGoogle Scholar
  214. 214.
    Savoia C, Touyz RM, Amiri F, Schiffrin EL. Selective mineralocorticoid receptor blocker eplerenone reduces resistance artery stiffness in hypertensive patients. Hypertension. 2008;51:432–9.PubMedGoogle Scholar
  215. 215.
    Yoshida C, Goda A, Naito Y, et al. Role of plasma aldosterone concentration in regression of left-ventricular mass following antihypertensive medication. J Hypertens. 2011;29:357–63.PubMedGoogle Scholar
  216. 216.
    Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309:781–91.PubMedGoogle Scholar
  217. 217.
    Shah SJ, Heitner JF, Sweitzer NK, et al. Baseline characteristics of patients in the treatment of preserved cardiac function with an aldosterone antagonist trial. Circ Heart Fail. 2013;6:184–92.PubMedGoogle Scholar
  218. 218.
    Bochud M, Nussberger J, Bovet P, et al. Plasma aldosterone is independently associated with the metabolic syndrome. Hypertension. 2006;48:239–45.PubMedGoogle Scholar
  219. 219.
    Remuzzi G, Cattaneo D, Perico N. The aggravating mechanisms of aldosterone on kidney fibrosis. J Am Soc Nephrol. 2008;19:1459–62.PubMedGoogle Scholar
  220. 220.
    Pratt-Ubanama MN, Nishizaka MK, Boedefeld RL, et al. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest. 2007;131:453–9.Google Scholar
  221. 221.
    Tomaschitz A, Pilz S, Ritz E, et al. Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk and Cardiovascular (LURIC) health study. Eur Heart J. 2010;31:1237–47.PubMedGoogle Scholar
  222. 222.
    Ivanes F, Susen S, Mouquet F, et al. Aldosterone, mortality, and acute ischemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure. Eur Heart J. 2012;33:191–202.PubMedGoogle Scholar
  223. 223.
    Edwards NC, Steeds RP, Stewart PM, et al. Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial. J Am Coll Cardiol. 2009;54:505–12.PubMedGoogle Scholar
  224. 224.
    Fujita T. Mineralocorticoid receptors, salt-sensitive hypertension, and metabolic syndrome. Hypertension. 2010;55:813–8.PubMedGoogle Scholar
  225. 225.
    Mosso LM, Carvajal CA, Maiz A, et al. A possible association between primary aldosteronism and a lower beta-cell function. Hypertension. 2007;25:2125–30.Google Scholar
  226. 226.
    Leopold JA, Dam A, Maron BA, et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med. 2007;13:189–97.PubMedCentralPubMedGoogle Scholar
  227. 227.
    Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system. Ann NY Acad Sci. 2002;970:89–100.PubMedGoogle Scholar
  228. 228.
    Callera GE, Touyz RM, Tostes RC, et al. Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension. 2005;45:773–9.PubMedGoogle Scholar
  229. 229.
    Usher MG, Duan SZ, Ivaschenko CY, et al. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J Clin Invest. 2010;120:3350–64.PubMedCentralPubMedGoogle Scholar
  230. 230.
    Keidar S, Gamliel-Lazarovich A, Kaplan M, et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res. 2005;97:946–53.PubMedGoogle Scholar
  231. 231.
    Yamamuro M, Yoshimura M, Nakayama M, et al. Aldosterone, but not angiotensin II, reduces angiotensin converting enzyme 2 gene expression levels in cultured neonatal rats cardiomyocytes. Circ J. 2008;72:1346–50.PubMedGoogle Scholar
  232. 232.
    Swedberg K, Zannad F, McMurray JJ, et al. EMPHASIS-HF Study Investigators. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (eplerenone in mild patients hospitalization and survival study in heart failure) study. J Am Coll Cardiol. 2012;59:1598–603.PubMedGoogle Scholar
  233. 233.
    Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49:355–64.PubMedGoogle Scholar
  234. 234.
    Schupp N, Kolkhof P, Queisser N, et al. Mineralocorticoid receptor-mediated DNA damage in kidneys of DOCA-salt hypertensive rats. FASEB J. 2011;25:968–78.PubMedGoogle Scholar
  235. 235.
    Zhang Y-L, Zhou S-X, Lei J, Yuan G-Y, Wang J-F. Blockades of angiotensin and aldosterone reduce osteopontin expression and interstitial fibrosis infiltration in rats with myocardial infarction. Chin Med J. 2008;121:2192–6.PubMedGoogle Scholar
  236. 236.
    Qin W, Rudolph AE, Bond BR, et al. Transgenic model of aldosterone–driven cardiac hypertrophy and heart failure. Circ Res. 2003;93:69–76.PubMedGoogle Scholar
  237. 237.
    Messaoudi S, Milliez P, Samuel JL, Delcayre C. Cardiac aldosterone overexpression prevents harmful effects of diabetes in the mouse heart by preserving capillary density. FASEB J. 2009;23:2176–85.PubMedGoogle Scholar
  238. 238.
    Lother A, Berger S, Gilsbach R, et al. Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function. Hypertension. 2011;57:746–54.PubMedGoogle Scholar
  239. 239.
    Palmer BF. Managing hyperkalemia caused by inhibition of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351:585–92.PubMedGoogle Scholar
  240. 240.
    Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ, the PEARL-HF investigators. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J. 2011;32:820–8.PubMedGoogle Scholar
  241. 241.
    van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158998 patients. Eur Heart J. 2012;33:2088–97.PubMedGoogle Scholar
  242. 242.
    Unger T, Paulis L, Sica DA. Therapeutic perspectives in hypertension: novel means for renin-angiotensin-aldosterone system modulation and emerging device-based approaches. Eur Heart J. 2011;32:2739–47.PubMedGoogle Scholar
  243. 243.
    Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51:1403–19.PubMedGoogle Scholar
  244. 244.
    Werner C, Poss J, Bohm M. Optimal antagonism of the renin-angiotensin-aldosterone system: do we need dual or triple therapy? Drugs. 2010;70:1215–30.PubMedGoogle Scholar
  245. 245.
    Amar L, Azizi M, Menard J, et al. Aldosterone synthase inhibition with LCI699. A proof-of-concept study in patients with primary aldosteronism. Hypertension. 2010;56:831–8.PubMedGoogle Scholar
  246. 246.
    Fiebeler A, Nussberger J, Shagdarsuren E, et al. Aldosterone synthase inhibitor ameliorates angiotensin-II induced organ damage. Circulation. 2005;111:3087–94.PubMedGoogle Scholar
  247. 247.
    Lea WB, Kwak ES, Luther JM, et al. Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt. Kidney Int. 2009;75:936–44.PubMedCentralPubMedGoogle Scholar
  248. 248.
    Mulder P, Mellin V, Favre J, et al. Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone. Eur Heart J. 2008;29:2171–9.PubMedGoogle Scholar
  249. 249.
    Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension. 2002;39:E1–8.PubMedGoogle Scholar
  250. 250.
    Dietz R, Dechend R, Yu CM, et al. Effects of the direct renin inhibitor aliskiren and atenolol alone or in combination in patients with hypertension. J Renin Angiotensin Aldosterone Syst. 2008;9:163–75.PubMedGoogle Scholar
  251. 251.
    Schmieder RE, Philipp T, Guerediaga J, et al. Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide. Circulation. 2009;119:417–25.PubMedGoogle Scholar
  252. 252.
    Andersen K, Weinberger MH, Egan B, et al. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial. J Hypertens. 2008;26:589–99.PubMedGoogle Scholar
  253. 253.
    Duprez DA, Munger MA, Botha J, Keefe DL, Charney AN. Aliskiren for geriatric lowering of systolic hypertension: a randomized controlled trial. J Hum Hypertens. 2010;24:600–8.PubMedGoogle Scholar
  254. 254.
    Stanton A, Jensen C, Nussberger J, O’Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension. 2003;42:1137–43.PubMedGoogle Scholar
  255. 255.
    Menard J, Campbell DJ, Azizi M, Gonzales MF. Synergistic effects of ACE inhibition and AngII antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats. Circulation. 1997;96:3072–8.PubMedGoogle Scholar
  256. 256.
    Sealey JE, Laragh JH. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness. Am J Hypertens. 2007;20:587–97.PubMedGoogle Scholar
  257. 257.
    Schefe JH, Neumann C, Goebel M, et al. Prorenin engages the pro(renin) receptor like renin and both ligand activities are unopposed by aliskiren. J Hypertens. 2008;26:1787–94.PubMedGoogle Scholar
  258. 258.
    Westermann D, Riad A, Lettau O, et al. Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure. Hypertension. 2008;52:1068–75.PubMedGoogle Scholar
  259. 259.
    McMurray JJV, Pitt B, Latini R, et al. Effects of the oral renin inhibitor aliskiren in patients with symptomatic HF. Circ Heart Fail. 2008;1:17–24.PubMedGoogle Scholar
  260. 260.
    Gheorghiade M, Albaghdadi M, Zannad F, et al. On behalf of the ASTRONAUT investigators and study coordinators. Rationale and design of the multicentre, randomized, double-blind, placebo-controlled aliskiren trial on acute heart failure outcomes (ASTRONAUT). Eur J Heart Fail. 2011;13:100–6.PubMedGoogle Scholar
  261. 261.
    Krum H, Massie B, Abraham WT, et al. ATMOSPHERE investigators. Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the aliskiren trial to minimize outcomes in patients with heart failure (ATMOSPHERE) study. Eur J Heart Fail. 2011;13:107–14.PubMedGoogle Scholar
  262. 262.
    Solomon SD, Shin SH, Shah A, et al. Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) Investigators. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Eur Heart J. 2011;32:1227–34.PubMedGoogle Scholar
  263. 263.
    Rasilez® ASPIRE HIGHER Clinical Program Expands to 35,000 Patients in 14 Trials, The Largest Cardio-renal Outcomes Program Ever. Medical News Today, 20 June 2008. Accessed 31 July 2013.
  264. 264.
    Parving HH, Persson F, Lewis JB, et al. AVOID study investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–46.PubMedGoogle Scholar
  265. 265.
    Parving HH, Brenner BM, McMurray JJ, et al. ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204–22.PubMedGoogle Scholar
  266. 266.
    Solomon SD, Skali H, Bourgoun M, et al. Effect of angiotensin-converting enzyme or vasopeptidase inhibition on ventricular size and function in patients with heart failure: the omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE) echocardiographic study. Am Heart J. 2005;150:257–62.PubMedGoogle Scholar
  267. 267.
    Solomon SD, Zile M, Pieske B, et al. Prospective comparison of ARNI with ARB on Management Of heart failure with preserved ejectioN fracTion. PARAMOUNT investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized clinical trial. Lancet. 2012;380(9851):1387–95.PubMedGoogle Scholar
  268. 268.
    McMurray JJ, Packer M, Desai AS, et al. On behalf of the PARADIGM-HF Committees and Investigators. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in patients with heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2013;15:1062–73.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.2C2 W.C. Mackenzie Health Sciences Centre, Division of Cardiology, Department of MedicineMazankowski Alberta Heart Institute, University of Alberta and HospitalsEdmontonCanada

Personalised recommendations