Prehypertension: A Case in Favor of Early Use of Diuretics

  • Flávio Danni FuchsEmail author
  • Sandra Costa Fuchs
Part of the Updates in Hypertension and Cardiovascular Protection book series (UHCP)


Blood pressure (BP) thresholds to diagnose hypertension and to guide therapy have faced ups and downs in recent years. As anticipated by this chapter, the recently released American College of Cardiology and American Heart Association guidelines of hypertension promoted the full range of diastolic BP of prehypertension to hypertension (≥80 mmHg), and established that systolic BP ≥ 130 mmHg is also a criterion to diagnosis hypertension. Meta-analyses identified an unequivocal benefit of BP-lowering drugs in preventing major cardiovascular events in patients with prehypertension. The SPRINT trial added another piece of evidence that treatment with a systolic BP goal below 120 mmHg reduces the incidence of major cardiovascular events and all-cause mortality. Diuretics, particularly chlorthalidone, are the drugs with the best record in terms of prevention of major cardiovascular outcomes in well-designed and unbiased clinical trials. The two more relevant adverse effects of thiazide diuretics are linked, since hypokalemia is the major cause of blood glucose increasing. The association of potassium-sparing agents is the more rational approach to prevent both adverse effects, contributing also with some BP-lowering effect.


Prehypertension Diuretics Chlorthalidone Potassium-sparing diuretics 


  1. 1.
    James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high BP in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–20.PubMedCrossRefGoogle Scholar
  2. 2.
    Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. ESH/ESC Guidelines for the management of arterial hypertension. J Hypertens. 2013;2013(31):1281–57.CrossRefGoogle Scholar
  3. 3.
    Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA, Clinical Guidelines Committee of the American College of Physicians and the Commission on Health of the Public and Science of the American Academy of Family Physicians. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166(6):430–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Leung AA, Nerenberg K, Daskalopoulou SS, McBrien K, Zarnke KB, Dasgupta K, et al. Hypertension Canada’s 2016 Canadian hypertension education program guidelines for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. 2016;32(5):569–88.PubMedCrossRefGoogle Scholar
  5. 5.
    Gabb GM, Mangoni AA, Anderson CS, Cowley D, Dowden JS, Golledge J, et al. Guideline for the diagnosis and management of hypertension in adults – 2016. Med J Aust. 2016;205(2):85–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Fisher JW. The diagnostic value of the sphygmomanometer in examinations for life insurance. JAMA. 1914;63:1752–4.CrossRefGoogle Scholar
  7. 7.
    White P. Heart disease. 2nd ed. New York, NY: McMillan Co; 1937. p. 326.Google Scholar
  8. 8.
    Prospective Studies Collaboration. Age-specific relevance of usual BP to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–13.CrossRefGoogle Scholar
  9. 9.
    Fuchs FD. Essentials of hypertension. New york: Springer; 2017.Google Scholar
  10. 10.
    Moreira LB, Fuchs SC, Wiehe M, Gus M, Moraes RS, Fuchs FD. Incidence of hypertension in Porto Alegre, Brazil: a population-based study. J Hum Hypertens. 2008;22:48–50.PubMedCrossRefGoogle Scholar
  11. 11.
    Takashima N, Ohkubo T, Miura K, Okamura T, Murakami Y, Fujiyoshi A, et al., NIPPON DATA80 Research Group. Long-term risk of BP values above normal for cardiovascular mortality: a 24-year observation of Japanese aged 30 to 92 years. J Hypertens. 2014;32:236–44.CrossRefGoogle Scholar
  12. 12.
    Markus MR, Stritzke J, Lieb W, Mayer B, Luchner A, Döring A, et al. Implications of persistent prehypertension for ageing-related changes in left ventricular geometry and function: the MONICA/KORA Augsburg study. J Hypertens. 2008;26:2040–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Santos AB, Gupta DK, Bello NA, Gori M, Claggett B, Fuchs FD, et al. Prehypertension is associated with abnormalities of cardiac structure and function in the atherosclerosis risk in communities study. Am J Hypertens. 2016;29:568–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med. 2005;165(8):923–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Kanno A, Kikuya M, Ohkubo T, Hashimoto T, Satoh M, Hirose T, et al. Pre-hypertension as a significant predictor of chronic kidney disease in a general population: the Ohasama Study. Nephrol Dial Transplant. 2012;27:3218–23.PubMedCrossRefGoogle Scholar
  16. 16.
    The 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.CrossRefGoogle Scholar
  17. 17.
    The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–53.CrossRefGoogle Scholar
  18. 18.
    Fox KM, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–41.CrossRefGoogle Scholar
  20. 20.
    The SOLVD investigators. Effect of enalapril on mortality and development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–91.CrossRefGoogle Scholar
  21. 21.
    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;325:669–77.CrossRefGoogle Scholar
  22. 22.
    Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, 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 Eng J Med. 1992;327:669–77.CrossRefGoogle Scholar
  23. 23.
    The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 1987;316:1429–35.CrossRefGoogle Scholar
  24. 24.
    Fuchs FD. Blood pressure-lowering drugs: essential therapy for some patients with normal BP. Expert Rev Cardiovasc Ther. 2004;2:771–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Law MR, Morris JK, Wald NJ. Use of BP lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:B1665.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA. Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA. 2011;305:913–22.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Fuchs FD. Prehypertension: the rationale for early drug therapy. Cardiovasc Ther. 2010;28:339–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Fuchs FD, de Mello RB, Fuchs SC. Preventing the progression of prehypertension to hypertension: role of antihypertensives. Curr Hypertens Rep. 2015;17:505.PubMedCrossRefGoogle Scholar
  29. 29.
    Fuchs FD, Fuchs SC. Blood pressure targets in the treatment of high BP: a reappraisal of the J-shaped phenomenon. J Hum Hypertens. 2014;28:80–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387:957–67.PubMedCrossRefGoogle Scholar
  31. 31.
    Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive BP lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:43543.Google Scholar
  32. 32.
    Thomopoulos C, Parati G, Zanchetti A. Effects of BP lowering on outcome incidence in hypertension: 7. Effects of more vs. less intensive BP lowering and different achieved BP levels updated overview and meta-analyses of randomized trials. J Hypertens. 2016;34:613–22.PubMedCrossRefGoogle Scholar
  33. 33.
    SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–16.CrossRefGoogle Scholar
  34. 34.
    Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, et al. Intensive vs standard BP control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315:2673–82.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Bundy JD, Li C, Stuchlik P, Bu X, Kelly TN, Mills KT, et al. Systolic blood pressure reduction and risk of cardiovascular disease and mortality. JAMA Cardiol. 2017;2(7):775–81.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al., Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354:1685–97.PubMedCrossRefGoogle Scholar
  37. 37.
    Lüders S, Schrader J, Berger J, Unger T, Zidek W, Böhm M, et al., PHARAO Study Group. The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal BP – a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens. 2008;26:1487–96.PubMedCrossRefGoogle Scholar
  38. 38.
    Fuchs SC, Poli-de-Figueiredo Carlos E, Figueiredo-Neto JA, Scala LC, Whelton PK, Mosele F, et al. Effectiveness of chlorthalidone plus amiloride for the prevention of hypertension: The PREVER PREVENTION Randomized Clinical Trial. J Am Heart Assoc. 2016;e004248:5.Google Scholar
  39. 39.
    MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–7.CrossRefGoogle Scholar
  40. 40.
    Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362:7–13.PubMedCrossRefGoogle Scholar
  41. 41.
    SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1991;265:3255–64.CrossRefGoogle Scholar
  42. 42.
    Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al., HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887–98.PubMedCrossRefGoogle Scholar
  43. 43.
    Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, et al. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation. 2008;118(22):2259–67.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al., SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21(5):875–86.CrossRefGoogle Scholar
  45. 45.
    Yusuf S, Sleight P, Anderson C, Teo K, Copland I, Ramos B, et al., TRANSCEND Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. Lancet. 2008;372(9644):1174–83.PubMedCrossRefGoogle Scholar
  46. 46.
    Yusuf S, Diener HC, Sacco RL, Cotton D, Ôunpuu S, Lawton WA, et al., PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359(12):1225–37.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    McMurray JJ, Holman RR, Haffner SM, Bethel A, Holzhauer B, Hua TA, et al., NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16):1477–90.PubMedCrossRefGoogle Scholar
  48. 48.
    Yusuf S, Healey JS, Pogue J, Chrolavicius S, Flather M, Hart RG, et al., ACTIVE I Investigators. Irbesartan in patients with atrial fibrillation. N Engl J Med. 2011;364(10):928–38.PubMedCrossRefGoogle Scholar
  49. 49.
    Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, et al., ROADMAP Trial Investigators. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364(10):907–17.PubMedCrossRefGoogle Scholar
  50. 50.
    Imai E, Chan JC, Ito S, Yamasaki T, Kobayashi F, Haneda H, et al., ORIENT study investigators. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia. 2011;54(12):2978–86.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Bangalore S, Kumar S, Wetterslev J, Messerli FH. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. BMJ. 2011;342:d2234.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    van Vark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, Boersma E. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158 998 patients. Eur Heart J. 2012;33:2088–97.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Cheng J, Zhang W, Zhang X, Han F, Li X, He X, Li Q, Chen J. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med. 2014;174:773–85.PubMedCrossRefGoogle Scholar
  54. 54.
    Elgendy IY, Huo T, Chik V, Pepine CJ, Bavry AA. Efficacy and safety of angiotensin receptor blockers in older patients: a meta-analysis of randomized trials. Am J Hypertens. 2015;28:576–85.PubMedCrossRefGoogle Scholar
  55. 55.
    Bangalore S, Fakheri R, Wandel S, Toklu B, Wandel J, Messerli FH. Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials. BMJ. 2017;356:j4.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs--overview and meta-analyses. J Hypertens. 2015;33(2):195–211.PubMedCrossRefGoogle Scholar
  57. 57.
    Retraction. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet. 2009;374(9697):1226.CrossRefGoogle Scholar
  58. 58.
    Retraction. Valsartan in a Japanese population with hypertension and other cardiovascular disease (JIKEI HEART STUDY): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet. 2013;382(9895):843.CrossRefGoogle Scholar
  59. 59.
    Retraction. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J. 2013;34(14):1023.CrossRefGoogle Scholar
  60. 60.
    Fuchs FD. The role of angiotensin receptor blockers in the prevention of cardiovascular and renal disease: time for reassessment? Evid Based Med. 2013;18:44–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Fuchs FD, DiNicolantonio JJ. Angiotensin receptor blockers for prevention of cardiovascular disease: where does the evidence stand? Open Heart. 2015;2:e000236.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Tobian L. Evidence for Na-retaining humoral agents and vasoconstrictor humoral agents in hypertension-prone Dahl ‘S’ rats. Prevention of NaCl-induced hypertension in Dahl ‘S’ rats with thiazide. Horm Res. 1979;11(6):277–91.PubMedCrossRefGoogle Scholar
  63. 63.
    ALLHAT Officers. Major cardiovascular events in hypertensive patients randomized to doxazosin vs. chlorthalidone. JAMA. 2000;283:1967–75.CrossRefGoogle Scholar
  64. 64.
    The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA. 2002;288(23):2981–97.CrossRefGoogle Scholar
  65. 65.
    Psaty BM, Lumley T, Furberg CD. Meta-analysis of health outcomes of chlorthalidone-based vs non-chlorthalidone-based low-dose diuretic therapies. JAMA. 2004;292(1):43–4.PubMedCrossRefGoogle Scholar
  66. 66.
    Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension. 2012;59:1110–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 2011;57:689–94.PubMedCrossRefGoogle Scholar
  68. 68.
    Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006;47(3):352–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Messerli FH, Makani H, Benjo A, Romero J, Alviar C, Bangalore S. Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring: a meta-analysis of randomized trials. J Am Coll Cardiol. 2011;57(5):590–600.PubMedCrossRefGoogle Scholar
  70. 70.
    Peterzan MA, Hardy R, Chaturvedi N, Hughes AD. Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bendroflumethiazide on blood pressure, serum potassium, and urate. Hypertension. 2012;59:1104–9.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Pareek AK, Messerli FH, Chandurkar NB, Dharmadhikari SK, Godbole AV, Kshirsagar PP, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambulatory blood pressure monitoring. J Am Coll Cardiol. 2016;67(4):379–89.PubMedCrossRefGoogle Scholar
  72. 72.
    Franse LV, Pahor M, Di Bari M, Somes GW, Cushman WC, Applegate WB. Hypokalemia associated with diuretic use and cardiovascular events in the systolic hypertension in the elderly program. Hypertension. 2000;35(5):1025–30.PubMedCrossRefGoogle Scholar
  73. 73.
    Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension. 2006;48(2):1–6.CrossRefGoogle Scholar
  74. 74.
    Guerrero P, Fuchs FD, Moreira LM, Martins VM, Bertoluci C, Fuchs SC, et al. Blood pressure-lowering efficacy of amiloride versus enalapril as add-on drugs in patients with uncontrolled blood pressure receiving hydrochlorothiazide. Clin Exp Hypertens. 2008;30(7):553–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Brown MJ, Williams B, Morant SV, Webb DJ, Caulfield MJ, Cruickshank JK, et al. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial. Lancet Diabetes Endocrinol. 2016;4(2):136–47.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J. 1992;304:405–12.CrossRefGoogle Scholar
  77. 77.
    Brown MJ, Palmer CR, Castaigne A, Leew PW, Mancia G, Rosenthal T, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study (INSIGHT). Lancet. 2000;356(9227):366–72.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Cardiology, Hospital de Clínicas de Porto Alegre, School of MedicineUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Graduate Program in Cardiology, School of MedicineUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

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