Advertisement

Heart Failure Reviews

, Volume 13, Issue 3, pp 367–375 | Cite as

Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies

  • John W. WrightEmail author
  • Shigehiko Mizutani
  • Joseph W. Harding
Article

Abstract

The renin-angiotensin-aldosterone system (RAAS) is critical in regulating systemic blood pressure, water and electrolyte balance, and pituitary gland hormones. These physiologies appear to be primarily mediated by the angiotensin II/AT1 receptor subtype system. Overstimulation of this system can predispose cardiovascular disease (CVD) characterized by excessive vasoconstriction, fibrosis, and cardiac remodeling. If untreated, the patient typically displays a continuum of pathophysiologic conditions progressing from atherosclerosis to left ventricle hypertrophy (LVH), coronary thrombosis, myocardial infarcts, with heart failure as an endpoint. Intervention with antihypertensive therapy is necessary to inhibit this progression. RAAS blocking drugs appear to be the most effective approach. Diastolic heart failure patients benefit from treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin AT1 receptor blockers (ARBs). Elderly CVD patients evidence age-related changes in body composition that alter the distribution and half-life of medications, thus presenting special challenges to treatment. The presence of comorbidities such as diabetes, renal dysfunction, liver insufficiency further complicates any therapeutic strategy. In addition, noncompliance because of cognitive impairment, depression, confusion due to the complexity of dose regimens, and lack of an appropriate social support system can disrupt positive outcome. The present review discusses the roles of an overactive RAAS and sympathetic nervous system as primary contributors to CVD. In addition, treatment strategies are discussed, focusing on middle aged and elderly hypertensive and heart failure patients.

Keywords

Cardiovascular disease Renin-angiotensin-aldosterone system AT1 receptor subtype Extracellular matrix Pharmaceutical treatment strategies 

Notes

Acknowledgments

The research from our laboratory presented in this review was supported by NIH grant RO1-HL64245-03, NSF grant IBN-0091337, and the Edward E. and Lucille I. Lainge Endowment for Alzheimer’s Research. We thank Mrs. Ruth Day for secretarial assistance provided during the course of writing this manuscript.

References

  1. 1.
    Dzau V, Braunwald E (1991) Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 121:1244–1263PubMedCrossRefGoogle Scholar
  2. 2.
    Dzau V (2005) The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens 23:S9–S17CrossRefGoogle Scholar
  3. 3.
    Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J, Popma JJ, Stevenson W (2006) The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes. Part I: pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation 114:2850–2870PubMedCrossRefGoogle Scholar
  4. 4.
    Baker KM, Booz GW, Dostal DE (1992) Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol 54:227–241PubMedCrossRefGoogle Scholar
  5. 5.
    Mehta PK, Griendling KK (2006) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292:C82–C97PubMedCrossRefGoogle Scholar
  6. 6.
    Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M et al (2000) Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 101:1372–1378PubMedGoogle Scholar
  7. 7.
    Adams KF (2004) Pathophysiologic role of the renin-angiotensin-aldosterone and sympathetic nervous systems in heart failure. Am J Health Syst Pharm 61(Suppl 2):S4–S13PubMedGoogle Scholar
  8. 8.
    Unger T (2002) The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 89:3A–10APubMedCrossRefGoogle Scholar
  9. 9.
    Schena M, Mulatero P, Schiavone D, Mengozzi G, Tesio L, Chiandussi L, Veglio F (1999) Vasoactive hormones induce nitric oxide synthase mRNA expression and nitric oxide production in human endothelial cells and monocytes. Am J Hypertens 12:388–397PubMedGoogle Scholar
  10. 10.
    Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotortone. J Clin Invest 97:1916–1923PubMedCrossRefGoogle Scholar
  11. 11.
    Kalra D, Sivasubramanian N, Mann DL (2002) Angiotensin II induces tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C-dependent pathway. Circulation 105: 2198–2205PubMedCrossRefGoogle Scholar
  12. 12.
    Feener EP, Northrup JM, Aiello LP, King GL (1995) Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells. J Clin Invest 95:1353–1362PubMedCrossRefGoogle Scholar
  13. 13.
    Wright JW, Harding JW (2004) The brain angiotensin system and extracellular matrix molecules in neural plasticity, learning, and memory. Prog Neurobiol 72:263–293PubMedCrossRefGoogle Scholar
  14. 14.
    Lips DJ, deWindt LJ, van Kraaij DJ, Doevendans PA (2003) Molecular determinants of myocardial hypertrophy and failure: alternative pathways for beneficial and maladaptive hypertrophy. Eur Heart J 24:883–896PubMedCrossRefGoogle Scholar
  15. 15.
    Lombardi D, Gordon KL, Polinsky P, Suga S, Schwartz SM, Johnson RJ (1999) Salt-sensitive hypertension develops after short-term exposure to Angiotensin II. Hypertension 33:1013–1019PubMedGoogle Scholar
  16. 16.
    Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Suzuki Y, Mezzano S et al (2001) Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension 38:1382–1387PubMedCrossRefGoogle Scholar
  17. 17.
    Yamada H, Fabris B, Allen AM, Jackson B, Johnston CI, Mendelsohn AO (1995) Localization of angiotensin converting enzyme in rat heart. Circ Res 68:141–149Google Scholar
  18. 18.
    Falkenhahn M, Franke F, Bohle RM, Zhu YC, Stauss HM, Bachmann S et al (1995) Cellular distribution of angiotensin-converting enzyme after myocardial infarction. Hypertension 25:219–226PubMedGoogle Scholar
  19. 19.
    Leri A, Claudio PP, Li Q (1998) Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J Clin Invest 101:1326–1342PubMedCrossRefGoogle Scholar
  20. 20.
    Ruzicka M, Skarda V, Leenen FH (1995) Effects of ACE inhibitors on circulating versus cardiac angiotensin II in volume overload-induced cardiac hypertrophy in rats. Circulation 92:3568–3573PubMedGoogle Scholar
  21. 21.
    Schunkert H, Ingelfinger JR, Hirsch AT (1992) Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure. J Clin Invest 90:1523–1529PubMedCrossRefGoogle Scholar
  22. 22.
    Lee YA, Liang CS, Lee MA, Lindpaintner K (1996) Local stress, not systemic factors, regulate gene expression of the cardiac renin-angiotensin system in vivo: a comprehensive study of all its components in the dog. Proc Natl Acad Sci USA 93:11035–11040PubMedCrossRefGoogle Scholar
  23. 23.
    Schluter KD, Wollert KC (2004) Synchronization and integration of multiple hypertrophic pathways in the heart. Cardiovasc Res 63:367–372PubMedCrossRefGoogle Scholar
  24. 24.
    Pagliaro P, Penna C (2005) Rethinking the renin-angiotensin system and its role in cardiovascular regulation. Cardiovasc Drugs & Therapy 19:77–87CrossRefGoogle Scholar
  25. 25.
    Thomas WG, Brandenburger Y, Autelitano DJ, Pham T, Qian H, Hannan RD (2002) Adenoviral-directed expression of the type 1A angiotensin receptor promotes cardiomyocyte hypertrophy via transactivation of the epidermal growth factor receptor. Circ Res 90:135–142PubMedCrossRefGoogle Scholar
  26. 26.
    Pellieux C, Foletti A, Peduto G, Aubert JF, Nussberger J, Beermann F et al (2001) Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2. J Clin Invest 108:1843–1851PubMedGoogle Scholar
  27. 27.
    Xia Y, Karmazyn M (2004) Obligatory role for endogenous endothelin in mediating the hypertrophic effects of phenylephrine and angiotensin II in neonatal rat ventricular myocytes: evidence for two distinct mechanisms for endothelin regulation. J Pharmacol Exp Ther 310:43–51PubMedCrossRefGoogle Scholar
  28. 28.
    Kato H, Suzuki H, Tajima S, Ogata Y, Tominaga T, Sato A, Saruta T (1991) Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens 9:17–22PubMedGoogle Scholar
  29. 29.
    Mifune M, Ohtsu H, Suzuki H, Nakashima H, Brailoiu E, Dun NJ et al (2005) Protein coupling and second messenger generation are indispensable for metalloprotease-dependent, heparin binding epidermal growth factor shedding through angiotensin II type-1 receptor. J Biol Chem 80:26592–26599CrossRefGoogle Scholar
  30. 30.
    Fields RD, Itoh K (1996) Neural cell adhesion molecules in activity-dependent development and synaptic plasticity. Trends Neurosci 19:473–480PubMedCrossRefGoogle Scholar
  31. 31.
    Schachner M (1997) Neural recognition molecules and synaptic plasticity. Curr Opin Cell Biol 9:627–634PubMedCrossRefGoogle Scholar
  32. 32.
    Stamenkovic I (2003) Extracellular matrix remodeling: the role of matrix metalloproteinases. J Pathol 200:448–464PubMedCrossRefGoogle Scholar
  33. 33.
    Jeng A, Gonnell N, Skiles J (2001) The design, structure, and therapeutic application of matrix metalloproteinase inhibitors. Curr Med Chem 8:425–474PubMedGoogle Scholar
  34. 34.
    Osler W (1992) The principle and practice of medicine. Appleton and Company, New York, pp 628–635Google Scholar
  35. 35.
    Gradman AH, Alfayoumi F (2006) From left ventricular hypertophy to congestive heart failure: management of hypertensive heart disease. Prog Cardiovasc Dis 48:326–341CrossRefGoogle Scholar
  36. 36.
    Eichhorn EJ, Bristow MR (1996) Medical therapy can improve the biological properties of the chronically failing heart: a new era in the treatment of heart failure. Circulation 94:2285–2296PubMedGoogle Scholar
  37. 37.
    Wright JW, Harding JW (2006) Angiotensins in brain function. In: Lim R (ed) Handbook of neurochemistry and molecular neurobiology: neuroactive proteins and peptides. Springer Science, New York, pp 627–653Google Scholar
  38. 38.
    Stanton A (2003) Potential of renin inhibition in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 4:6–10PubMedCrossRefGoogle Scholar
  39. 39.
    Johnston CI (1990) Biochemistry and pharmacologyof the renin-angiotensin system. Drugs 39:21–31PubMedCrossRefGoogle Scholar
  40. 40.
    Zisman ID, Abraham WT, Meiixell GE (1995) Angiotensin II formation in the intact human heart. Predominance of the angiotensin converting enzyme pathway. J Clin Invest 96:1490–1498PubMedCrossRefGoogle Scholar
  41. 41.
    Dell’Italia IJ, Sabri A (2004) Activation of the renin-angiotensin system in hypertrophy and heart failure. In: Mann DL (ed) Heart Failure. Saunders, Philadelphia PA, pp 63–76Google Scholar
  42. 42.
    Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA (1997) 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 99:1926–1935PubMedCrossRefGoogle Scholar
  43. 43.
    Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT (1990) Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 67:1355–1364PubMedGoogle Scholar
  44. 44.
    Sabbah HN, Stein PD, Kono T, Gheorghiade M, Levine TB, Jafri S et al (1991) A canine model of chronic heart failure produced by multiple sequential coronary microembolizations. Am J Physiol 260:H1379–H1384PubMedGoogle Scholar
  45. 45.
    McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J et al (1999) 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 100:1056–1064PubMedGoogle Scholar
  46. 46.
    Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B et al (2003) Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 108:1831–1838PubMedCrossRefGoogle Scholar
  47. 47.
    Hayashida W, Donckier J, Van Mechelen H, Charlier AA, Pouleur H (1997) Diastolic properties in canine hypertensive left ventricular hypertrophy: effects of angiotensin converting enzyme inhibition and angiotensin II type-1 receptor blockade. Cardiovasc Res 33:54–62PubMedCrossRefGoogle Scholar
  48. 48.
    Wachtell K, Bella JN, Rokkedal J, Palmieri V, Papademetriou V, Dahlof B et al (2002) Change in diastolic left ventricular filing after one year of antihypertensive treatment: the losartan intervention for endpoint reduction in hypertension (LIFE) study. Circulation 105:1071–1076PubMedCrossRefGoogle Scholar
  49. 49.
    Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Ubago J (2002) Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105:2512–2517PubMedCrossRefGoogle Scholar
  50. 50.
    Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ et al (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 362:777–781PubMedCrossRefGoogle Scholar
  51. 51.
    Levy D, Anderson KM, Savage DD, Kannel WB, Christiansen JC, Castelli WP (1988) Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The framingham heart study. Ann Intern Med 108:7–13PubMedGoogle Scholar
  52. 52.
    Bulpitt CJ, Cameron JD, Rajkumar C, Armstrong S, Connor M, Joshi J et al (1999) The effect of age on vascular compliance in man: which are the appropriate measures? J Hum Hypertens 13:753–758PubMedCrossRefGoogle Scholar
  53. 53.
    Svanborg A (1997) Age-related changes in cardiac physiology. Can they be postponed or treated by drugs? Drugs Aging 10:463–472PubMedCrossRefGoogle Scholar
  54. 54.
    Beckett NS, Connor M, Sadler JD, Fletcher AE, Bulpitt CJ (1999) Orthostatic fall in blood pressure in the very elderly hypertensive: results from the hypertension in the very elderly trial (HYVET)––pilot. J Hum Hypertens 13:839–840PubMedCrossRefGoogle Scholar
  55. 55.
    Cleophas TJ, van Marum R (2003) Age-related decline in autonomic control of blood pressure: implications for the pharmacological management of hypertension in the elderly. Drugs Aging 20:313–319PubMedCrossRefGoogle Scholar
  56. 56.
    Belmin J, Levy BI, Michel JB (1994) Changes in the renin-angiotensin-aldosterone axis in later life. Drugs Aging 5:391–400PubMedGoogle Scholar
  57. 57.
    Takeda R, Morimoto S, Uchida K, Miyamori I, Hashiba T (1980) Effect of age on plasma aldosterone response to exogenous angiotensin II in normotensive subjects. Acta Endocrinol 94:552–558PubMedGoogle Scholar
  58. 58.
    Dulin BR, Krum H (2006) Drug therapy of chronic heart failure in the elderly: the current state of clinical-trial evidence. Curr Opin Cardiol 21:393–399PubMedCrossRefGoogle Scholar
  59. 59.
    Grady KL (2006) Management of heart failure in older adults. J Cardiovasc Nurs 21:S10–S14PubMedGoogle Scholar
  60. 60.
    Hunt SA, Abraham WT, Chin MH (2005) ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult. J Am Coll Cardiol. 46:1–82CrossRefGoogle Scholar
  61. 61.
    Mangoni AA (2005) Cardiovascular drug therapy in elderly patients: specific age-related pharmacokinetic, pharmacodynamic and therapeutic considerations. Drugs Aging 22:913–941PubMedCrossRefGoogle Scholar
  62. 62.
    Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA (2004) Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 351:543–551PubMedCrossRefGoogle Scholar
  63. 63.
    Dunbar-Jacob J, Bohichick P, Mortimer MK, Sereika SM, Foley SM (2003) Medication adherence in persons with cardiovascular disease. J Cardiovasc Nurs 18:209–218PubMedGoogle Scholar
  64. 64.
    Stuart-Shor EM, Buselli EF, Carroll DL, Forman DE (2003) Are psychosocial factors associated with the pathogenesis and consequences of cardiovascular disease in the elderly? J Cardiovasc Nurs 18:169–183PubMedCrossRefGoogle Scholar
  65. 65.
    Trenkwalder P (2002) Potential for antihypertensive treatment with an AT1-receptor blocker to reduce dementia in the elderly. J Hum Hypertens 16:S71–S75PubMedCrossRefGoogle Scholar
  66. 66.
    Aronow WS (2006) Heart failure update: treatment of heart failure with a normal left ventricular ejection fraction in the elderly. Geriatrics 61:16–20PubMedGoogle Scholar
  67. 67.
    Aronow WS (2007) Treatment of heart failure with abnormal left ventricular systolic function in the elderly. Clin Geriatr Med 23:61–81PubMedCrossRefGoogle Scholar
  68. 68.
    Kim S, Iwao H (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 52:11–34PubMedGoogle Scholar
  69. 69.
    Schmieder RE, Martus P, Klingeil A (1996) Reversal of left ventricular hypertrophy in essential hypertension: a meta-analysis of randomized double-blind studies. JAMA 275:1507–1523PubMedCrossRefGoogle Scholar
  70. 70.
    O’Connor CM, Arumugham P (2007) Inotropic drugs and neurohormonal antagonists in the treatment of HF in the elderly. Clin Geriatr Med 23:141–153PubMedCrossRefGoogle Scholar
  71. 71.
    Thomas GN, Chan P, Tomlinson B (2006) The role of angiotensin II type 1 receptor antagonists in elderly patients with hypertension. Drugs Aging 23:131–155PubMedCrossRefGoogle Scholar
  72. 72.
    Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE (2003) A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 115:41–46PubMedCrossRefGoogle Scholar
  73. 73.
    Sharpe M, Jarvis B, Goa KL (2001) Telmisartan: a review of its use in hypertension. Drugs 61:1501–1529PubMedCrossRefGoogle Scholar
  74. 74.
    Simpson KL, McClellan KJ (2000) Losartan: a review of its use, with special focus on elderly patients. Drugs Aging 16:227–250PubMedCrossRefGoogle Scholar
  75. 75.
    Warner GT, Jarvis B (2002) Olmesartan medoxomil. Drugs 62:1345–1353PubMedCrossRefGoogle Scholar
  76. 76.
    Lip GY, Beevers DG (2003) More evidence on blocking the renin-angiotensin-aldosterone system in cardiovascular disease and the long-term treatment of hypertension: data from recent clinical trials (CHARM, EUROPA, ValHEFT, HOPE-TOO and SYST-EUR2). J Hum Hypertens 17:747–750PubMedCrossRefGoogle Scholar
  77. 77.
    Unger T, Li J (2004) The role of the renin-angiotensin-aldosterone system in heart failure. J Renin Angiotensin Aldosterone Syst 5:S7–S10PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • John W. Wright
    • 1
    • 2
    • 3
    Email author
  • Shigehiko Mizutani
    • 4
  • Joseph W. Harding
    • 1
    • 2
    • 3
  1. 1.Department of PsychologyWashington State UniversityPullmanUSA
  2. 2.Department of Veterinary and Comparative Anatomy, Pharmacology, and PhysiologyWashington State UniversityPullmanUSA
  3. 3.Programs in Neuroscience and BiotechnologyWashington State UniversityPullmanUSA
  4. 4.Department of Medical Science of Proteases, Graduate School of MedicineNagoya UniversityNagoyaJapan

Personalised recommendations