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Resistant or Refractory Hypertension: Are They Different?

  • Resistant Hypertension (E Pimenta, Section Editor)
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Abstract

Resistant hypertension (RHTN) consists in a condition where blood pressure (BP) levels remain uncontrolled despite the use of at least three drugs or if the control happens with four or more drugs. Throughout the last 50 years, it has been increasingly studied, and its phenotypes have been identified. The term refractory hypertension has been used concurrently with RHTN all those years, but in the last decade, it has been applied to the most afflicted part of RHTN—defined as the uncontrolled RHTN or as the uncontrolled RHTN who needs five or more drugs. Differences between those two phenotypes are being recently identified, especially classifying refractory subjects as having more: (1) cardiovascular risk, (2) target organ damage, (3) African-descending race, (4) coronary heart disease and myocardial ischemia, (5) aldosterone excess, (6) deregulation of adipokines, and (7) possible sympathetic hyperactivation. We review the most important studies in both resistant and refractory hypertension to gather the up-to-date data regarding the characteristics of these two high-risk groups of patients.

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References

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  1. Vandyne JR. Iproniazid in the treatment of resistant hypertension—a preliminary-report on 20 intractable cases. J Am Geriatr Soc. 1960;8(6):454–62.

    CAS  Google Scholar 

  2. Lee RE, Seligmann AW, Clark MA, Borhani NO, Queenan JT, Obrien ME. Therapeutically refractory hypertension - causative factors, and medical management with chlorothiazide and other agents. Ann Intern Med. 1958;49(5):1129–37.

    Article  PubMed  CAS  Google Scholar 

  3. Heller R. Merriam-Webster Inc. Merriam-Webster’s first dictionary. Springfield, Mass.: Merriam-Webster; 2012.

  4. Gifford RW, Tarazi RC. Resistant hypertension—diagnosis and management. Ann Intern Med. 1978;88(5):661–5.

    Article  PubMed  Google Scholar 

  5. Gifford RW. Resistant hypertension—introduction and definitions. Hypertension. 1988;11(3):S65–6.

    Google Scholar 

  6. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, 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(6):1403–19. doi:10.1161/Hypertensionaha.108.189141.

    Article  PubMed  CAS  Google Scholar 

  7. Martell N, Rodriguez-Cerrillo M, Grobbee DE, Lopez-Eady MD, Fernandez-Pinilla C, Avila M, et al. High prevalence of secondary hypertension and insulin resistance in patients with refractory hypertension. Blood Press. 2003;12(3):149–54. doi:10.1080/08037050310009950.

    Article  PubMed  CAS  Google Scholar 

  8. Ram CVS. Review of resistant hypertension. Curr Hypertens Rep. 2006;8(5):398–402. doi:10.1007/s11906-006-0085-9.

    Article  PubMed  CAS  Google Scholar 

  9. Silverstein RL, Ram CVS. Resistant hypertension. Prim Care. 2008;35(3):501. doi:10.1016/j.pop.2008.03.002.

    Article  PubMed  Google Scholar 

  10. Sander GE, Giles TD. Resistant hypertension: concepts and approach to management. Curr Hypertens Rep. 2011;13(5):347–55. doi:10.1007/s11906-011-0226-7.

    Article  PubMed  Google Scholar 

  11. Acelajado MC, Pisoni R, Dudenbostel T, Dell’Italia LJ, Cartmill F, Zhang B, et al. Refractory hypertension: definition, prevalence, and patient characteristics. J Clin Hypertens. 2012;14(1):7–12. doi:10.1111/j.1751-7176.2011.00556.x. This manuscript analyzed 304 patients with resistant hypertension, finding the prevalence and characteristic of the 29 that were classified as presenting refractory hypertension. Interestingly, although the groups had similar aldosterone levels, the response to spironolactone was higher in resistant ones.

    Article  Google Scholar 

  12. Moreno H, Coca A. Resistant and refractory hypertension: reflections on pathophysiology and terminology. Blood Press. 2012;21(4):209–10. doi:10.3109/08037051.2012.701419.

    Article  PubMed  Google Scholar 

  13. Calhoun DA, Booth 3rd JN, Oparil S, Irvin MR, Shimbo D, Lackland DT, et al. Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large, population-based cohort. Hypertension. 2013. 2014; 63(3):451–8 doi:10.1161/HYPERTENSIONAHA.113.02026. This work evaluated 14,809 subjects from the REGARDS study, dividing them in resistant (controlled and uncontrolled) and refractory hypertension - with the proposed new definition, acknowledging some predictors of refractoriness comparing to resistant hypertension.

  14. Veglio F, Rabbia F, Riva P, Martini G, Geneva GC, Milan A, et al. Ambulatory blood pressure monitoring and clinical characteristics of the true and white-coat resistant hypertension. Clin Exp Hypertens. 2001;23(3):203–11. doi:10.1081/Ceh-100102660.

    Article  PubMed  CAS  Google Scholar 

  15. Verdecchia P. Using out of office blood pressure monitoring in the management of hypertension. Curr Hypertens Rep. 2001;3(5):400–5.

    Article  PubMed  CAS  Google Scholar 

  16. Modolo R, Ruggeri Barbaro N, de Faria AP, Rodrigues Sabbatini A, Paganelli MO, Fontana V, et al. The white-coat effect is an independent predictor of myocardial ischemia in resistant hypertension. Blood Press. 2014. doi:10.3109/08037051.2014.883194.

    Google Scholar 

  17. Pierdomenico SD, Lapenna D, Bucci A, Di Tommaso R, Di Mascio R, Manente BM, et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens. 2005;18(11):1422–8. doi:10.1016/j.amhyper.2005.05.014.

    Article  PubMed  Google Scholar 

  18. Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635–U112. doi:10.1161/Circulationaha.111.068064. This large retrospective cohort, evaluating 250,750 subjects showed an incidence of 1.9 % of resistant hypertension after 1.5 years of treatment. A more extensive follow-up revealed a higher risk of cardiovascular events in these resistant patients.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sim JJ, Bhandari SK, Shi JX, Liu ILA, Calhoun DA, McGlynn EA, et al. Characteristics of resistant hypertension in a large, ethnically diverse hypertension population of an integrated health system. Mayo Clin Proc. 2013;88(10):1099–107. doi:10.1016/j.mayocp.2013.06.017.

    Article  PubMed  Google Scholar 

  20. Cuspidi C, Macca G, Sampieri L, Michev I, Salerno M, Fusi V, et al. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens. 2001;19(11):2063–70. doi:10.1097/00004872-200111000-00018.

    Article  PubMed  CAS  Google Scholar 

  21. Martins LC, Figueiredo VN, Quinaglia T, Boer-Martins L, Yugar-Toledo JC, Martin JFV, et al. Characteristics of resistant hypertension: ageing, body mass index, hyperaldosteronism, cardiac hypertrophy and vascular stiffness. J Hum Hypertens. 2011;25(9):532–8. doi:10.1038/Jhh.2010.95.

    Article  PubMed  CAS  Google Scholar 

  22. Howard VJ, Cushman M, Pulley L, Gomez CR, Go RC, Prineas RJ, et al. The reasons for geographic and racial differences in stroke study: objectives and design. Neuroepidemiology. 2005;25(3):135–43. doi:10.1159/000086678.

    Article  PubMed  Google Scholar 

  23. Ubaid-Girioli S, de Souza LA, Yugar-Toledo JC, Martins LC, Ferreira-Melo S, Coelho OR, et al. Aldosterone excess or escape: treating resistant hypertension. J Clin Hypertens. 2009;11(5):245–52. doi:10.1111/j.1751-7176.2009.00110.x.

    Article  CAS  Google Scholar 

  24. de Faria APC, Demacq C, Figueiredo VN, Moraes CH, Santos RC, Sabbatini AR, et al. Hypoadiponectinemia and aldosterone excess are associated with lack of blood pressure control in subjects with resistant hypertension. Hypertens Res. 2013;36(12):1067–72. doi:10.1038/Hr.2013.92.

    Article  PubMed  Google Scholar 

  25. Salles GF, Fiszman R, Cardoso CRL, Muxfeldt ES. Relation of left ventricular hypertrophy with systemic inflammation and endothelial damage in resistant hypertension. Hypertension. 2007;50(4):723–8. doi:10.1161/Hypertensionaha.107.093120.

    Article  PubMed  CAS  Google Scholar 

  26. de Faria APC, Fontana V, Modolo R, Barbaro NR, Sabbatini AR, Pansani IF, et al. Plasma 8-isoprostane levels are associated with endothelial dysfunction in resistant hypertension. Clin Chim Acta. 2014;433:179–83. doi:10.1016/j.cca.2014.03.009.

    Article  PubMed  Google Scholar 

  27. Brambilla G, Bombelli M, Seravalle G, Cifkova R, Laurent S, Narkiewicz K, et al. Prevalence and clinical characteristics of patients with true resistant hypertension in central and Eastern Europe: data from the BP-CARE study. J Hypertens. 2013;31(10):2018–24. doi:10.1097/Hjh.0b013e328363823f.

    Article  PubMed  CAS  Google Scholar 

  28. Egan BM, Zhao Y, Li J, Brzezinski WA, Todoran TM, Brook RD, et al. Prevalence of optimal treatment regimens in patients with apparent treatment-resistant hypertension based on office blood pressure in a community-based practice network. Hypertension. 2013;62(4):691–7. doi:10.1161/HYPERTENSIONAHA.113.01448.

    Article  PubMed  CAS  Google Scholar 

  29. Gijon-Conde T, Graciani A, Banegas JR. Resistant hypertension: demography and clinical characteristics in 6292 patients in a primary health care setting. Rev Esp Cardiol. 2014. doi:10.1016/j.recesp.2013.09.029.

    PubMed  Google Scholar 

  30. Gupta AK, Nasothimiou EG, Chang CL, Sever PS, Dahlof B, Poulter NR, et al. Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J Hypertens. 2011;29(10):2004–13. doi:10.1097/Hjh.0b013e32834a8a42. This analysis of the previous ASCOT study showed significant determinants of developing resistant hypertension such as systolic blood pressure, diabetes, left ventricular hypertrophy, male gender, obesity, fasting glucose, and alcohol intake. Hence the randomization for the statin use group reduced the risk of developing resistant hypertension.

    Article  PubMed  CAS  Google Scholar 

  31. Fontana V, de Faria AP, Barbaro NR, Sabbatini AR, Modolo R, Lacchini R, et al. Modulation of aldosterone levels by −344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension. J Am Soc Hypertens. 2013. doi:10.1016/j.jash.2013.12.001.

    PubMed  Google Scholar 

  32. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke, and coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335(8692):765–74.

    Article  PubMed  CAS  Google Scholar 

  33. Wong ND, Lopez VA, L’Italien G, Chen R, Kline SE, Franklin SS. Inadequate control of hypertension in US adults with cardiovascular disease comorbidities in 2003–2004. Arch Intern Med. 2007;167(22):2431–6. doi:10.1001/archinte.167.22.2431.

    Article  PubMed  Google Scholar 

  34. Allman KG, Muir A, Howell SJ, Hemming AE, Sear JW, Foex P. Resistant hypertension and preoperative silent-myocardial-ischemia in surgical patients. Brit J Anaesth. 1994;73(5):574–8. doi:10.1093/Bja/73.5.574.

    Article  PubMed  CAS  Google Scholar 

  35. Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54(4):690–7. doi:10.1161/HYPERTENSIONAHA.108.119883.

    Article  PubMed  CAS  Google Scholar 

  36. Anderson EA, Sinkey CA, Lawton WJ, Mark AL. Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension. 1989;14(2):177–83.

    Article  PubMed  CAS  Google Scholar 

  37. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998;31(1):68–72.

    Article  PubMed  CAS  Google Scholar 

  38. DiBona GF. Nervous kidney—interaction between renal sympathetic nerves and the renin-angiotensin system in the control of renal function. Hypertension. 2000;36(6):1083–8.

    Article  PubMed  CAS  Google Scholar 

  39. Ferrario CM, Gildenberg PL, McCubbin JW. Cardiovascular effects of angiotensin mediated by the central nervous system. Circ Res. 1972;30(3):257–62.

    Article  PubMed  CAS  Google Scholar 

  40. Grassi G, Seravalle G, Dell’Oro R, Trevano FQ, Bombelli M, Scopelliti F, et al. Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. J Hypertens. 2003;21(9):1761–9. doi:10.1097/01.hjh.0000084718.53355.69.

    Article  PubMed  CAS  Google Scholar 

  41. Vasan RS, Evans JC, Larson MG, Wilson PWF, Meigs JB, Rifai N, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004;351(1):33–41. doi:10.1056/Nejmoa033263.

    Article  PubMed  CAS  Google Scholar 

  42. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among with resistant black and white subjects hypertension. Hypertension. 2002;40(6):892–6. doi:10.1161/01.Hyp.0000040261.30455.B6.

    Article  PubMed  CAS  Google Scholar 

  43. Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP. Low-renin status in therapy-resistent hypertension: a clue to efficient treatment. J Hypertens. 2004;22(11):2217–26. doi:10.1097/00004872-200411000-00026.

    Article  PubMed  CAS  Google Scholar 

  44. Umpierrez GE, Cantey P, Smiley D, Palacio A, Temponi D, Luster K, et al. Primary aldosteronism in diabetic subjects with resistant hypertension. Diabetes Care. 2007;30(7):1699–703. doi:10.2337/Dc07-0031.

    Article  PubMed  CAS  Google Scholar 

  45. Sabbatini AR, Faria AP, Barbaro NR, Gordo WM, Modolo RG, Pinho C, et al. Deregulation of adipokines related to target organ damage on resistant hypertension. J Hum Hypertens. 2013. doi:10.1038/jhh.2013.118.

    Google Scholar 

  46. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, et al. Characterization of resistant hypertension—association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008;168(11):1159–64. doi:10.1001/archinte.168.11.1159.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Menon DV, Arbique D, Wang Z, Adams-Huet B, Auchus RJ, Vongpatanasin W. Differential effects of chlorthalidone versus spironolactone on muscle sympathetic nerve activity in hypertensive patients. J Clin Endocrinol Metab. 2009;94(4):1361–6. doi:10.1210/Jc.2008-2660.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393–401. doi:10.1056/Nejmoa1402670.

    Article  PubMed  CAS  Google Scholar 

  49. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150(11):776–83.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Caprio M, Feve B, Claes A, Viengchareun S, Lombes M, Zennaro MC. Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis. Faseb J. 2007;21(9):2185–94. doi:10.1096/fj.06-7970com.

    Article  PubMed  CAS  Google Scholar 

  51. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548–56. doi:10.1210/jc.2004-0395.

    Article  PubMed  CAS  Google Scholar 

  52. Guo C, Ricchiuti V, Lian BQ, Yao TM, Coutinho P, Romero JR, et al. Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines. Circulation. 2008;117(17):2253–61. doi:10.1161/CIRCULATIONAHA.107.748640.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Moraes CD, Figueiredo VN, de Faria APC, Barbaro NR, Sabbatini AR, Quinaglia T, et al. High-circulating leptin levels are associated with increased blood pressure in uncontrolled resistant hypertension. J Hum Hypertens. 2013;27(4):225–30. doi:10.1038/Jhh.2012.29.

    Article  Google Scholar 

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Rodrigo Modolo, Ana Paula de Faria, Aurélio Almeida, and Heitor Moreno declare that they have no conflict of interest.

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  1. Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences, University of Campinas, FCM 10 Building, 1st Floor, Campinas, SP, Brazil, 13083-970

    Rodrigo Modolo, Ana Paula de Faria, Aurélio Almeida & Heitor Moreno

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  1. Rodrigo Modolo
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Correspondence to Heitor Moreno.

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This article is part of the Topical Collection on Resistant Hypertension

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Modolo, R., de Faria, A.P., Almeida, A. et al. Resistant or Refractory Hypertension: Are They Different?. Curr Hypertens Rep 16, 485 (2014). https://doi.org/10.1007/s11906-014-0485-1

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