Resistant arterial hypertension: clinical and pathogenetic peculiarities and predictors of therapy effectiveness

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L. A. Mishchenko
O. G. Kupchynska
O. O. Matova
K. I. Serbeniuk
O. V. Gulkevych


The aim – to evaluate the features of the target organs damage, neurohumoral and proinflammatory status and to determine the predictors of the effectiveness of antihypertensive therapy in patients with resistant arterial hypertension (RAH).
Materials and methods. The study included 257 patients with apparent RAH. The secondary hypertension was revealed in 8.5 % of patients. After 3 months therapy with triple fixed-dose combination (FDC) of antihypertensive drugs in maximum tolerated doses, patients were distributed into two groups – true RAH (n=103) and patients with pseudo resistant AH (PRAH) (n=132). We performed the comparative analysis of clinical characteristics, target organ damage degree, features of neurohumoral (plasma concentration of aldosterone and active renin, 24 – hour urinary metanephrines) and proinflammatory (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor – α (TNF-α) in plasma) status among groups. The predictors of effectiveness of the 4th antihypertensive drug addition (spironolactone, eplerenone, nebivоlol, moxonidine) to triple FDC in patients with RAH were studied.
Results and discussion. Higher levels of office and ambulatory blood pressure (BP), frequent (up to 14 %) disturbance of BP rhythm as night-peaker type, high BP morning surge are typical for RAH patients. 95 % of RAH patients had concentric left ventricular hypertrophy and 80 % – carotid atherosclerosis, a lower glomerular filtration rate and higher level of urinary albumin excretion rate (UAER). RAH patients had higher level of CRP – by 17.3 % (p=0.02), IL-6 –
by 21.8 % (p=0.01), TNF-α – by 13 % (p=0.003) in comparison with PRAH patients. The predictors of spironolactone and eplerenone efficacy are plasma aldosterone concentration (β=0.653; p=0.002), aldosterone-renin ratio (β=0.542; p=0.003), UAE (β=–0.362; p=0.01) and the level of CRP (β=–0.315; p=0.03).
Conclusions. Higher level of BP, target organ damage, more expressed activation of low – grade inflammation, sympathetic and renin-aldosterone-angiotensin systems activity are typical for RAH patients. The most effective drugs in addition to three – component FDC are MRA – spironolactone and eplerenone, which lead to the achievement of target BP at 48.5 % and 46.9 % (according to office and ambulatory testing) RAH patients. Nebivolol application contributed to BP normalization at 39.7 % and moxonidine – at 41.2 % RAH patients.

Article Details


resistant arterial hypertension, triple fixed dose combination of antihypertensive drugs, target organs damage, spironolactone, eplerenone, nebivоlol, moxonidine


Barbaro NR, Fontana V, Modolo R, De Faria AP, Sabbatini AR, Fonseca FH, Anhe GF, Moreno H. Increased arterial stiffness in resistant hypertension is associated with inflammatory biomarkers. Blood Press. 2015 Feb;24(1):7–13. Epub 2014 Jul 25.

Calhoun D, White W. Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension. J Am Soc Hypertens 2008 Nov-Dec;2(6):462-8. Epub 2008 Jul 23

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM; American Heart Association Professional Education. 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. Circulation. 2008 Jun 24;117(25):e510–26.

Cortez AF, Muxfeldt ES, Cardoso CR, Salles GF. Prognostic value of C-reactive protein in resistant hypertension. Am J Hypertens. 2016 Aug;29(8):992–1000. Epub 2016 Feb 16.

Cuspidi C, Macca G, Sampieri L, Michev I, Salerno M, Fusi V, Severgnini B, Meani S, Magrini F, Zanchetti A. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens. 2001 Nov;19(11):2063–70.

Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, O'Connor PJ, Selby JV, Ho PM. Incidence and Prognosis of Resistant Hypertension in Hypertensive Patients. Circulation. Author manuscript; available in PMC 2013 Apr 3.Published in final edited form as: Circulation. 2012 Apr 3;125(13):1635–1642.Published online 2012 Feb 29.

Duprez DA. Role of the rennin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical. Journal of Hypertension. 2006;4(6):983–991,June,PMID: 16685192Issn Print: 0263-6352 Publication Date: June 2006

Frohlich ED. Classification of resistant hypertension. Hypertension. 1988 Mar;11(3 Pt 2):II67-70.

Gifford R.W. Resistant hypertension: introduction and definitions. Hypertension. 1988;11:1165–1166.

Kario K, Pickering TG, Umeda Yu, Hoshide S, Hoshide Yo, Morinari M, Murata M, Kuroda T, Schwartz JoE, and Shimada K. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensive patients. A prospective study. Circulation.2003;107:1401–1406 .

Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990 May 31;322(22):1561–6 .

Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F; Task Force Members. 2013 ESH/ESC 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). J Hypertens. 2013 Jul;31(7):1281–357.

Morisky ED, Alfonso A., Krousel-Wood M, Ward JH. Predictive Validity of a Medication Adherence Measure in an Outpatient Setting. Journal of clinical hypertension 2008;10:348–354. DOI:10.1111/j.1751-7176.2008.07572.x

Persell S. D. Prevalence of resistant hypertension in the United States, 2003 2008.Hypertension.2011Jun;57(6):107680. Epub 2011 Apr 18.

Pierdomenico SD, Lapenna D, Bucci A, Di Tommaso R, Di Mascio R, Manente BM, Caldarella MP, Neri M, Cuccurullo F, Mezzetti A. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. American Journal of Hypertension, 2005;18, Issue 11, November:1422–1428,

Smith SM. Epidemiology, prognosis, and treatment of resistant hypertension. Pharmacotherapy. 2013 Oct;33(10):1071-86. Epub 2013 May 30.

Tsioufis C, Kordalis A, Flessas D, Anastasopoulos I, Tsiachris D, Papademetriou V, Stefanadis C. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. Int J Hypertens. 2011; 2011: 642416. Published online 2011 Jan 20.

Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr., 2017. ACC/AHA/AAPA/ABC/ACPM/AGS/ APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension.2018Jun;71(6):1269–1324. Epub 2017 Nov 13.

Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I; ESC Scientific Document Group.2018 ESC/ESH Guidelines for the management of arterial hypertension. European Heart Journal, September 2018;39, Issue 33, 01:3021–3104,

Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ1; British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind,crossover trial. Lancet. 2015 Nov 21;386(10008):2059-2068. Epub 2015 Sep 20.

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