Advertisement

Cardiovascular Drugs and Therapy

, Volume 16, Issue 2, pp 149–160 | Cite as

Pathophysiologic and Therapeutic Importance of Tissue ACE: A Consensus Report

  • Victor J. Dzau
  • Kenneth Bernstein
  • David Celermajer
  • Jerome Cohen
  • Björn Dahlöf
  • John Deanfield
  • Javier Diez
  • Helmut Drexler
  • Roberto Ferrari
  • Wiek van Gilst
  • Lennart Hansson
  • Burkhard Hornig
  • Ahsan Husain
  • Colin Johnston
  • Harold Lazar
  • Eva Lonn
  • Thomas Lüscher
  • John Mancini
  • Albert Mimran
  • Carl Pepine
  • Ton Rabelink
  • Willem Remme
  • Luis Ruilope
  • Marcel Ruzicka
  • Heribert Schunkert
  • Karl Swedberg
  • Thomas Unger
  • Douglas Vaughan
  • Michael Weber
Article

Abstract

Angiotensin-converting enzyme (ACE) activation and the de novo production of angiotensin II contribute to cardiovascular disease through direct pathological tissue effects, including vascular remodeling and inflammation, as well as indirect action on nitric oxide bioavailability and its consequences. The endothelium plays a pivotal role in both vascular function and structure; thus, the predominant localization of ACE to the endothelium has implications for the pathobiology of vascular disease, such as coronary artery disease. Numerous experimental studies and clinical trials support the emerging realization that tissue ACE is a vital therapeutic target, and that its inhibition may restore endothelial function or prevent endothelial dysfunction. These effects exceed those attributable to blood pressure reduction alone; hence, ACE inhibitors may exert an important part of their effects through direct tissue action. Pharmacologic studies show that while ACE inhibitors may differ according to their binding affinity for tissue ACE the clinical significance remains to be determined.

tissue ACE angiotensin-converting enzyme inhibitors endothelial dysfunction cardiovascular disease 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Erdos EG, Skidgel RA. The angiotensin I-converting enzyme. Lab Invest1987;56:345–348.Google Scholar
  2. 2.
    Barrett A, Rawlings N, Woessner F. Introduction: Clan MG containing cobalt and zinc aminopeptidases. In: Barrett A, Rawlings N, Woessner F, eds. Handbook of Proteolytic Enzymes. New York: Academic Press, 1998:1407–1410.Google Scholar
  3. 3.
    Nash DT. Comparative properties of angiotensin-converting enzyme inhibitors: Relations with inhibition of tissue angiotensin-converting enzyme and potential clinical implications. Am J Cardiol1992;69:26C–32C.Google Scholar
  4. 4.
    Johnston CI. Tissue angiotensin converting enzyme in cardiac and vascular hypertrophy, repair, and remodeling. Hypertension1994;23:258–268.Google Scholar
  5. 5.
    Unger T, Gohlke P. Converting enzyme inhibitors in cardiovascular therapy: Current status and future potential. Cardiovasc Res1994;28:146–158.Google Scholar
  6. 6.
    Perich RB, Jackson B, Johnston CI. Structural constraints of inhibitors for binding at two active sites on somatic angiotensin converting enzyme. Eur J Pharmaco 1994;266:201–211.Google Scholar
  7. 7.
    Ng KKF, Vane JR. Fate of angiotensin I in the circulation. Nature1968;218:144–150.Google Scholar
  8. 8.
    Cushman DW, Cheung HS. Concentrations of angiotensinconverting enzyme in tissues of the rat. Biochim Biophys Acta 1971;250:261–265.Google Scholar
  9. 9.
    Bernstein KE. The role of tissue angiotensin-converting enzyme (ACE): Studies of ACE mutant mice. Am J Cardiol 1998;82:5S–7S.Google Scholar
  10. 10.
    Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation. J Clin Invest 1990;86:1913–1920.Google Scholar
  11. 11.
    Yamada H, Fabris B, Allen AM, Jackson B, Johnston CI, Mendelsohn AO. Localization of angiotensin converting enzyme in rat heart. Circ Res 1991;68:141–149.Google Scholar
  12. 12.
    Holubarsch C, Hasenfuss G, Schmidt-Schweda S, et al. Angiotensin I and II exert inotropic effects in atrial but not in ventricular human myocardium. An in vitro study under physiological experimental conditions. Circulation 1993;88:1228–1237.Google Scholar
  13. 13.
    Pieruzzi F, Abassi ZA, Keiser HR. Expression of reninangiotensin system components in the heart, kidneys, and lungs of rats with experimental heart failure. Circulation 1995;92:3105–3112.Google Scholar
  14. 14.
    Ruzicka M, Skarda V, Leenen FH. Effects of ACE inhibitors on circulating versus cardiac angiotensin II in volume overload-induced cardiac hypertrophy in rats. Circulation1995;92:3568–3573.Google Scholar
  15. 15.
    Fabris B, Jackson B, Kohzuki M, Perich R, Johnston CI. Increased cardiac angiotensin-converting enzyme in rats with chronic heart failure. Clin Exp Pharmacol Physiol 1990;17:309–314.Google Scholar
  16. 16.
    Hirsch AT, Talsness CE, Schunkert H, Paul M, Dzau VJ. Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res 1991;69:475–482.Google Scholar
  17. 17.
    Hokimoto S, Yasue H, Fujimoto K, et al. Expression of angiotensin-converting enzyme in remaining viable myocytes of human ventricles after myocardial infarction. Circulation1996;94:1513–1518.Google Scholar
  18. 18.
    Lee YA, Liang CS, Lee MA, Lindpaintner K. 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 Sc 1996;93:11035–11040.Google Scholar
  19. 19.
    Heymes C, Swynghedauw B, Chevalier B. Activation of angiotensinogen and angiotensin-converting enzyme gene expression in the left ventricle of senescent rats. Circulation 1994;90:1328–1333.Google Scholar
  20. 20.
    Falkenhahn M, Franke F, Bohle RM, et al. Cellular distribution of angiotensin-converting enzyme after myocardial infarction. Hypertension 1995;25:219–226.Google Scholar
  21. 21.
    Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993;75:977–984.Google Scholar
  22. 22.
    Danser AH, Schalekamp MA. Is there an internal cardiac renin-angiotensin system? Heart 1996;76:28–32.Google Scholar
  23. 23.
    Danser AH, de Lannoy LM, Saxena P, Schalekamp MD.Chymase does not contribute to angiotensin I-II conversion in the interstitial fluid. Circulation 1998;98:I-793.Google Scholar
  24. 24.
    Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res 1990;66:883–890.Google Scholar
  25. 25.
    Muller DN, Fischli W, Clozel JP, et al. Local angiotensin II generation in the rat heart: Role of renin uptake. Circ Res 1998;82:13–20.Google Scholar
  26. 26.
    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 Chem1990;265:22348–22357.Google Scholar
  27. 27.
    Kokkonen JO, Saarinen J, Kovanen PT. Regulation of a local angiotensin II formation in the human heart in the presence of interstitial fluid. Inhibition of chymase by protease inhibitors of interstitial fluid and of angiotensin-converting enzyme by Ang-(1-9) formed by heart carboxypeptidase Alike activity. Circulation 1997;95:1455–1463.Google Scholar
  28. 28.
    Dzau VJ, Bernstein K, Celermajer D, et al. The relevance of tissue ACE: manifestations in mechanistic and endpoint data. The American Journal of Cardiology 2001;88.Google Scholar
  29. 29.
    Baker KM, Aceto JF. Angiotensin II stimulation of protein synthesis and cell growth in chick heart cells. Am J Physiol 1990;259:H610–H618.Google Scholar
  30. 30.
    Kromer EP, Riegger GA. Effects of long-term angiotensin converting enzyme inhibition on myocardial hypertrophy in experimental aortic stenosis in the rat. Am J Cardiol 1988;62:161–163.Google Scholar
  31. 31.
    Bruckschlegel G, Holmer SR, Jandeleit K, et al. Blockade of the renin-angiotensin system in cardiac pressure-overload hypertrophy in rats. Hypertension 1995;25:250–259.Google Scholar
  32. 32.
    Ruzicka M, Leenen FH. Relevance of blockade of cardiac and circulatory angiotensin-converting enzyme for the prevention of volume overload-induced cardiac hypertrophy. Circulation1995;91:16–19.Google Scholar
  33. 33.
    Lear W, Ruzicka M, Leenen FH. ACE inhibitors and cardiac ACE mRNA in volume overload-induced cardiac hypertrophy. Am J Physiol1997;273:H641–H646.Google Scholar
  34. 34.
    Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:1849–1865.Google Scholar
  35. 35.
    Katwa LC, Campbell SE,Tyagi SC, Lee SJ, Cicila GT, Weber KT. Cultured myofibroblasts generate angiotensin peptides de novo. J Mol Cell Cardiol 1997;29:1375–1386.Google Scholar
  36. 36.
    Anversa P, Cheng W, Liu Y, Leri A, Redaelli G, Kajstura J. Apoptosis and myocardial infarction. Basic Res Cardiol 1998;93:8–12.Google Scholar
  37. 37.
    Schunkert H, Jackson B, Tang SS, et al. Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts. Circulation 1993;87:1328–1339.Google Scholar
  38. 38.
    Friedrich SP, Lorell BH, Rousseau MF, et al. Intracardiac angiotensin-converting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis. Circulation 1994;90:2761–2771.Google Scholar
  39. 39.
    Weinberg EO, Schoen FJ, George D, et al. Angiotensinconverting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis. Circulation 1994;90:1410–1422.Google Scholar
  40. 40.
    Jackson EK, Garrison JC. Renin and angiotensin. In: Hardman JG, Limbird L, eds. Goodman & Gilman's the Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 1999:733–758.Google Scholar
  41. 41.
    Luscher TF, Barton M. Biology of the endothelium. Clin Cardiol 1997;20:II-3–10.Google Scholar
  42. 42.
    Cryer A. Scale and diversity of interaction at the vascular endothelium. In: Cryer A. ed. Biochemical Interaction of the Endothelium. Amsterdam: Elsevier Science, 1983: 1–3.Google Scholar
  43. 43.
    Rajagopalan S, Kurz S, Munzel T, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membraneNADH/NADPHoxidase activation. J Clin Invest 1996;97:1916–1923.Google Scholar
  44. 44.
    Marui N, Offermann MK, Swerlick R, et al. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 1993;92:1866–1874.Google Scholar
  45. 45.
    Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. Faseb J 1995;9:899–909.Google Scholar
  46. 46.
    Britten MB, Zeiher AM, Schachinger V. Clinical importance of coronary endothelial vasodilator dysfunction and therapeutic options. J Intern Med 1999;245:315–327.Google Scholar
  47. 47.
    Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol1999;31:51–60.Google Scholar
  48. 48.
    Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest 1995;95:995–1001.Google Scholar
  49. 49.
    Fishel RS, Eisenberg S, Shai SY, Redden RA, Bernstein KE, Berk BC. Glucocorticoids induce angiotensinconverting enzyme expression in vascular smooth muscle. Hypertension1995;25:343–349.Google Scholar
  50. 50.
    Peach MJ, Dostal DE. The angiotensin II receptor and the actions of angiotensin II. J Cardiovasc Pharmacol 1990;16:S25–S30.Google Scholar
  51. 51.
    Inagami T, Iwai N, Sasaki K, et al. Cloning, expression and regulation of angiotensin II receptors. J Hypertens 1992;10:713–716.Google Scholar
  52. 52.
    Bumpus FM, Catt KJ, Chiu AT, et al. Nomenclature for angiotensin receptors. A report of the Nomenclature Committee of the Council for High Blood Pressure Research. Hypertension1991;17:720–721.Google Scholar
  53. 53.
    Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998;339:1285–1292.Google Scholar
  54. 54.
    Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation 1997;95:1115–1118.Google Scholar
  55. 55.
    Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA.Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. Circulation 1997;96:442–447.Google Scholar
  56. 56.
    Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998;32:965–971.Google Scholar
  57. 57.
    Moroi M, Zhang L, Yasuda T, et al. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest 1998;101:1225–1232.Google Scholar
  58. 58.
    Pfeffer MA, Braunwald E, Moye 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;327:669–677.Google Scholar
  59. 59.
    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
  60. 60.
    The Acute Infraction Ramipril Efficacy Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821–828.Google Scholar
  61. 61.
    Torp-Pedersen C, Kober L. Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced leftventricular function after acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Lancet1999;354:9–12.Google Scholar
  62. 62.
    Johnston CI, Fabris B, Yamada H, et al. Comparative studies of tissue inhibition by angiotensin converting enzyme inhibitors. J Hypertens Suppl 1989;7:S11–S16.Google Scholar
  63. 63.
    Fabris B, Chen B, Pupic V, Perich R, Johnston CI. Inhibition of angiotensin-converting enzyme (ACE) in plasma and tissue. J Cardiovasc Pharmacol 1990;15:S6–S13.Google Scholar
  64. 64.
    Fabris B, Yamada H, Cubela R, Jackson B, Mendelsohn FA, Johnston CI. Characterization of cardiac angiotensin converting enzyme (ACE) and in vivo inhibition following oral quinapril to rats. Br J Pharmacol 1990;100:651–655.Google Scholar
  65. 65.
    Johnston CI, Fabris B, Yoshida K. The cardiac reninangiotensin system in heart failure. Am Heart J 1993;126:756–760.Google Scholar
  66. 66.
    Kinoshita A, Urata H, Bumpus FM, Husain A. Measurement of angiotensin I converting enzyme inhibition in the heart. Circ Res1993;73:51–60.Google Scholar
  67. 67.
    Opie LH. ACE inhibitors: specific agents and pharmacokinetics. In: Opie LH, ed. Angiotensin-Converting Enzyme Inhibitors: Scientific Basis for Clinical Use. New York: Wiley-Liss, 1994:171–217.Google Scholar
  68. 68.
    Ranadive SA, Chen AX, Serajuddin AT. Relative lipophilicities and structural-pharmacological considerations of various angiotensin-converting enzyme (ACE) inhibitors. Pharm Res1992;9:1480–1486.Google Scholar
  69. 69.
    Berkenboom G, Langer I, Carpentier Y, Grosfils K, Fontaine J. Ramipril prevents endothelial dysfunction induced by oxidized low-density lipoproteins: A bradykinin-dependent mechanism. Hypertension 1997;30:371–376.Google Scholar
  70. 70.
    Martorana PA, Ruetten H, Goebel B, et al. Ramiprilat prevents the development of acute coronary endothelial dysfunction in the dog. Basic Res Cardiol 1999;94:238–245.Google Scholar
  71. 71.
    Van Belle E, Meurice T, Tio FO, et al. ACE inhibition accelerates endothelial regrowth in vivo: A possible explanation for the benefit observed with ACE inhibitors following arterial injury. Biochem Biophys Res Commun 1997;231:577–581.Google Scholar
  72. 72.
    Varin R, Mulder P, Tamion F, et al. Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure: Role of nitric oxide, prostanoids, oxidant stress, and bradykinin. Circulation 2000;102:351–356.Google Scholar
  73. 73.
    Zhuo JL, Froomes P, Casley D, et al. Perindopril chronically inhibits angiotensin-converting enzyme in both the endothelium and adventitia of the internal mammary artery in patients with ischemic heart disease. Circulation 1997;96:174–182.Google Scholar
  74. 74.
    Lyons D, Webster J, Benjamin N. Effect of enalapril and quinapril on forearm vascularACEin man. Eur J Clin Pharmacol1997;51:373–378.Google Scholar
  75. 75.
    Hornig B, Arakawa N, Haussmann D, Drexler H. Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998;98:2842–2848.Google Scholar
  76. 76.
    Oosterga M, Voors AA, Buikema H, et al. Functional effects of ACE-inhibitors on angiotensin I conversion in human vasculature. J Am Coll Cardiol1998;2:239A(abstr).Google Scholar
  77. 77.
    Mancini GB, Henry GC, Macaya C, et al. Angiotensinconverting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing Endothelial Dysfunction) Study. Circulation 1996;94:258–265.Google Scholar
  78. 78.
    Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol 2000;35:60–66.Google Scholar
  79. 79.
    Ruilope LM, Miranda B, Oliet A, et al. Control of hypertension with the angiotensin converting enzyme inhibitor captopril reduces glomerular proteinuria. J Hypertens 1988;6 Suppl:S467–S469.Google Scholar
  80. 80.
    Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF. Effect of antihypertensive therapy on the kidney in patients with diabetes: A meta-regression analysis. Ann Intern Med 1993;118:129–138.Google Scholar
  81. 81.
    Gansevoort RT, de Zeeuw D, de Jong PE. Additive antiproteinuric effect of ACE inhibition and a low-protein diet in human renal disease. Nephrol Dial Transplant 1995;10:497–504.Google Scholar
  82. 82.
    Praga M, Hernandez E, Andres A, Leon M, Ruilope LM, Rodicio JL. Effects of body-weight loss and captopril treatment on proteinuria associated with obesity. Nephron 1995;70:35–41.Google Scholar
  83. 83.
    Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611–616.Google Scholar
  84. 84.
    Estacio RO, Schrier RW. Antihypertensive therapy in type 2 diabetes: Implications of the appropriate blood pressure control in diabetes (ABCD) trial. Am J Cardiol 1998;82:9R–14R.Google Scholar
  85. 85.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, For the Collaborative Study Group. The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456–1462.Google Scholar
  86. 86.
    Texter M, Lees RS, Pitt B, Dinsmore RE, Uprichard AC. The QUinapril Ischemic Event Trial (QUIET) design and methods: Evaluation of chronic ACE inhibitor therapy after coronary artery intervention. Cardiovasc Drugs Ther 1993;7:273–282.Google Scholar
  87. 87.
    Cashin-Hemphill L, Holmvang G, Chan RC, Pitt B, Dinsmore RE, Lees RS. Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: No answer yet. Am J Cardiol 1999;83:43–47.Google Scholar
  88. 88.
    HOPE 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;355:253–259.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Victor J. Dzau
    • 1
  • Kenneth Bernstein
    • 2
  • David Celermajer
    • 3
  • Jerome Cohen
    • 4
  • Björn Dahlöf
    • 5
  • John Deanfield
    • 6
  • Javier Diez
    • 7
  • Helmut Drexler
    • 8
  • Roberto Ferrari
    • 9
  • Wiek van Gilst
    • 10
  • Lennart Hansson
    • 11
  • Burkhard Hornig
    • 8
  • Ahsan Husain
    • 12
  • Colin Johnston
    • 13
  • Harold Lazar
    • 14
  • Eva Lonn
    • 15
  • Thomas Lüscher
    • 16
  • John Mancini
    • 17
  • Albert Mimran
    • 18
  • Carl Pepine
    • 19
  • Ton Rabelink
    • 20
  • Willem Remme
    • 21
  • Luis Ruilope
    • 22
  • Marcel Ruzicka
    • 23
  • Heribert Schunkert
    • 24
  • Karl Swedberg
    • 25
  • Thomas Unger
    • 26
  • Douglas Vaughan
    • 27
  • Michael Weber
    • 28
  1. 1.Department of MedicineBrigham Women's HospitalBostonUSA
  2. 2.Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlantaUSA
  3. 3.Department of MedicineUniversity of SydneySydneyAustralia
  4. 4.Department of Internal MedicineSaint Louis University School of MedicineSaint LouisUSA
  5. 5.Department of MedicineSahlgrenska University Hospital/OstraNilssonsbergSweden
  6. 6.Vascular Physiology UnitGreat Ormond Street Hospital for ChildrenLondonUnited Kingdom
  7. 7.Unidad de Fisiopatologia Vascular, Edificio de CienciasUniversidad de NavarraPampalonaSpain
  8. 8.Department of CardiologyMedizinische Hochschule HannoverHannoverGermany
  9. 9.Department of Clinical and Experimental MedicineNuove ClinicheCorso FerraraItaly
  10. 10.Department of Clinical PharmacologyUniversity Hospital GroningenGroningenThe Netherlands
  11. 11.Clinical Hypertension ResearchUniversity of UppsalaUppsalaSweden
  12. 12.Victor Chang Cardiac Research InstituteDarlinghurstSydneyAustralia
  13. 13.Baker InstituteMelbourneAustralia
  14. 14.Department of Cardiothoracic SurgeryBoston Medical CenterBostonUSA
  15. 15.Division of CardiologyHGH-McMaster ClinicHamiltonCanada
  16. 16.Division of CardiologyUniversity Hospital ZurichZurichSwitzerland
  17. 17.Department of MedicineVancouver General HospitalVancouverCanada
  18. 18.Medecine Interne et Hypertension Arterielle, Centre Hospitalier, UniversitaireHospital LapeyronieMontpellierFrance
  19. 19.Division of Cardiovascular MedicineUniversity of Florida GainesvilleGainesvilleUSA
  20. 20.Department of Internal MedicineUniversity Hospital UtrechtUtrechtThe Netherlands
  21. 21.Sticares Cardiovascular Research FnDRhoonThe Netherlands
  22. 22.Unidad de HypertensionHospital MadridSpain
  23. 23.University of Ottawa Heart InstituteOttawaCanada
  24. 24.Klinik und Poliklinik fur Innere Medizin IIRegensburgGermany
  25. 25.Sahlgrenska University Hospital/OstraGöteberg, Sweden
  26. 26.Christian-Albrechts-University KielKielGermany
  27. 27.Division of CardiologyVanderbilt University School of MedicineNashvilleUSA
  28. 28.Department of MedicineBrookdale HospitalBrooklynUSA

Personalised recommendations