rpcardioRational Pharmacotherapy in CardiologyРациональная Фармакотерапия в Кардиологии1819-64462225-3653«SILICEA-POLIGRAF» LLC10.20996/10.20996/1819-6446-2023-2918KDMMDCrpcardio-2918Research ArticleCURRENT QUESTIONS OF CLINICAL PHARMACOLOGYАКТУАЛЬНЫЕ ВОПРОСЫ КЛИНИЧЕСКОЙ ФАРМАКОЛОГИИParadigm shift on the role of mineralocorticoid receptor antagonists in hypertension therapyИзменение представлений о роли антагонистов минералокортикоидных рецепторов при лечении артериальной гипертонииhttps://orcid.org/0000-0002-8505-1848ГиляревскийС. Р.GilyarevskyS. R.

Гиляревский Сергей Руджерович

Москва

Sergey R. Gilyarevsky

Moscow

sgilarevsky@gmail.comhttps://orcid.org/0000-0001-6418-7060ЛадыгинаД. О.LadyginaD. O.

Ладыгина Дарья Олеговна

Москва

Daria O. Ladygina

Moscow

ladygina.do@gmail.comРоссийская медицинская академия непрерывного профессионального образования Минздрава РоссииРоссияRussian Medical Academy of Continuous Professional EducationRussian FederationПервый Московский государственный медицинский университет им. И.М. Сеченова Минздрава России (Сеченовский университет)РоссияI. M. Sechenov First Moscow State Medical UniversityRussian Federation202311072023194403412Copyright © Gilyarevsky S.R., Ladygina D.O., 20232023Гиляревский С.Р., Ладыгина Д.О.Gilyarevsky S.R., Ladygina D.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rpcardio.online/jour/article/view/2918

The literature review is devoted to modern ideas about the role of hyperaldosteronism as one of the important pathophysiological links in hypertension (HTN) development. Data are presented on aldosterone synthesis mechanisms both in healthy and sick people, in particular in primary aldosteronism (PA), as well as in some cases of secondary aldosteronism. The results of modern studies are discussed, which established autonomous formation of aldosterone in elderly and senile people even without formal criteria for PA. The most important stages of studying and solving the hyperaldosteronism problem using surgical or conservative methods areconsidered. Data are presented on target organ damage caused by an increased blood concentration of aldosterone. The influence of the interaction between increased dietary sodium intake and the severity of cardiovascular damage is discussed. Separately, the role of subclinical hyperaldosteronism in the development of hypertension is considered, as well as the possibility of target organ damage in such cases, despite the normal blood pressure level. Modern data on the role of mineralocorticoid receptor antagonists (MRAs), in particular spironolactone, in the treatment of hyperaldosteronism and resistant hypertension are presented. The limitations of MRA use, which are mainly due to reduced kidney function, are considered. In particular, the results of the most important clinical studies are discussed, which became the basis for higher prescription rate of MRAs in the treatment of hypertensive patients.

Обзор литературы посвящен современным представлениям о роли гиперальдостеронизма как одного из важных патофизиологических звеньев развития артериальной гипертонии (АГ). Приводятся данные о механизмах, регулирующих образование альдостерона в организме как в норме, так при патологии, в частности при первичном гиперальдостеронизме (ПГА), а также в некоторых случаях вторичного гиперальдостеронизма. Обсуждаются результаты современных исследований, в которых установлена возможность автономного образования альдостерона у лиц пожилого и старческого возраста даже в отсутствие формальных критериев ПГА. Рассматриваются наиболее важные этапы изучения проблемы гиперальдостеронизма и ее решения с помощью хирургических или медикаментозных методов. Представлены данные о механизмах поражения органов-мишеней, которые обусловлены повышенной концентрацией альдостерона в крови. Обсуждается влияние взаимодействия между повышенным потреблением натрия с пищей и выраженностью влияния гиперальдостеронизма на тяжесть поражения органов сердечно-сосудистой системы. Отдельно рассматривается роль субклинического гиперальдостеронизма в развитии АГ, а также о возможности в таких случаях поражения органов-мишеней, несмотря на нормальный уровень артериального давления. Приводятся современные данные о роли антагонистов минералокортикоидных рецепторов (АМКР), в частности спиронолактона, при лечении пациентов с гиперальдостеронизмом и резистентной АГ. Рассматриваются ограничения применения АМКР, которые в основном обусловлены сниженной функцией почек. В том числе обсуждаются результаты наиболее важных клинических исследований, которые стали основанием для более частого использования препаратов, относящихся к такому классу, при лечении пациентов с артериальной гипертензией.

 

гиперальдостеронизмартериальная гипертониярезистентная артериальная гипертензияантагонисты минералокортикоидных рецепторовспиронолактонhyperaldosteronismhypertensionresistant hypertensionmineralocorticoid receptor antagonistsspironolactoneСтатья подготовлена при поддержке компании Гедеон Рихтер, что не повлияло на мнение авторов.The article was prepared with the support of Gedeon Richter, which did not affect the independence of the opinion of the authors.ReferencesBuffolo F, Tetti M, Mulatero P, Monticone S. Aldosterone as a Mediator of Cardiovascular Damage. Hypertension. 2022;79(9):1899-1911. DOI:10.1161/ HYPERTENSIONAHA.122.17964.Buffolo F, Tetti M, Mulatero P, Monticone S. Aldosterone as a Mediator of Cardiovascular Damage. Hypertension. 2022;79(9):1899-1911. DOI:10.1161/ HYPERTENSIONAHA.122.17964.Gros R, Ding Q, Sklar LA, et al. GPR30 expression is required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone. Hypertension. 2011;57(3):442-451. DOI:10.1161/HYPERTENSIONAHA.110.161653.Gros R, Ding Q, Sklar LA, et al. GPR30 expression is required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone. Hypertension. 2011;57(3):442-451. DOI:10.1161/HYPERTENSIONAHA.110.161653.Buffolo F, Monticone S, Pecori A, et al. The spectrum of low-renin hypertension. Best Pract Res Clin Endocrinol Metab. 2020;34(3):101399. DOI:10.1016/j. beem.2020.101399.Buffolo F, Monticone S, Pecori A, et al. The spectrum of low-renin hypertension. Best Pract Res Clin Endocrinol Metab. 2020;34(3):101399. DOI:10.1016/j. beem.2020.101399.Rikimaru T, Fujita Y, Okuda T, et al. Responses of sodium balance, blood pressure, and other variables to sodium loading in Papua New Guinea highlanders. Am J Clin Nutr. 1988;47:502-508.Rikimaru T, Fujita Y, Okuda T, et al. Responses of sodium balance, blood pressure, and other variables to sodium loading in Papua New Guinea highlanders. Am J Clin Nutr. 1988;47:502-508.Brown JM, Robinson-Cohen C, Luque-Fernandez MA, et al. The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension: A Cohort Study. Ann Intern Med. 2017;167(9):630-641. DOI:10.7326/M17-0882.Brown JM, Robinson-Cohen C, Luque-Fernandez MA, et al. The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension: A Cohort Study. Ann Intern Med. 2017;167(9):630-641. DOI:10.7326/M17-0882.Oliver WJ, Cohen EL, Neel JV. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a “no-salt” culture. Circulation. 1975;52(1):146-151. DOI:10.1161/01.cir.52.1.146.Oliver WJ, Cohen EL, Neel JV. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a “no-salt” culture. Circulation. 1975;52(1):146-151. DOI:10.1161/01.cir.52.1.146.Jin Y, Kuznetsova T, Maillard M, et al. Independent relations of left ventricular structure with the 24-hour urinary excretion of sodium and aldosterone. Hypertension. 2009;54(3):489-495. DOI:10.1161/HYPERTENSIONAHA.109. 130492.Jin Y, Kuznetsova T, Maillard M, et al. Independent relations of left ventricular structure with the 24-hour urinary excretion of sodium and aldosterone. Hypertension. 2009;54(3):489-495. DOI:10.1161/HYPERTENSIONAHA.109. 130492.Catena C, Colussi G, Sechi LA. Aldosterone, organ damage and dietary salt. Clin Exp Pharmacol Physiol. 2013;40(12):922-928. DOI:10.1111/1440-1681.12145.Catena C, Colussi G, Sechi LA. Aldosterone, organ damage and dietary salt. Clin Exp Pharmacol Physiol. 2013;40(12):922-928. DOI:10.1111/1440-1681.12145.Funder JW. Aldosterone and Mineralocorticoid Receptors-Physiology and Pathophysiology. Int J Mol Sci. 2017;18(5):1032. DOI:10.3390/ijms18051032.Funder JW. Aldosterone and Mineralocorticoid Receptors-Physiology and Pathophysiology. Int J Mol Sci. 2017;18(5):1032. DOI:10.3390/ijms18051032.Nagata D, Takahashi M, Sawai K, et al. Molecular mechanism of the inhibitory effect of aldosterone on endothelial no synthase activity. Hypertension. 2006;48(1):165–171. DOI:10.1161/01.HYP.0000226054.53527.bb.Nagata D, Takahashi M, Sawai K, et al. Molecular mechanism of the inhibitory effect of aldosterone on endothelial no synthase activity. Hypertension. 2006;48(1):165–171. DOI:10.1161/01.HYP.0000226054.53527.bb.Leopold JA, Dam A, Maron BA, et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med. 2007;13(2):189-197. DOI:10.1038/nm1545.Leopold JA, Dam A, Maron BA, et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med. 2007;13(2):189-197. DOI:10.1038/nm1545.López-Andrés N, Martin-Fernandez B, Rossignol P, et al. A role for cardiotrophin-1 in myocardial remodeling induced by aldosterone. Am J Physiol Heart Circ Physiol. 2011;301(6):H2372-H2382. DOI:10.1152/ajpheart.00283.2011.López-Andrés N, Martin-Fernandez B, Rossignol P, et al. A role for cardiotrophin-1 in myocardial remodeling induced by aldosterone. Am J Physiol Heart Circ Physiol. 2011;301(6):H2372-H2382. DOI:10.1152/ajpheart.00283.2011.Burrello J, Gai C, Tetti M, et al. Characterization and gene expression analysis of serum-derived extracellular vesicles in primary aldosteronism. Hypertension. 2019;74(2):359-367. DOI:10.1161/HYPERTENSIONAHA.119.12944.Burrello J, Gai C, Tetti M, et al. Characterization and gene expression analysis of serum-derived extracellular vesicles in primary aldosteronism. Hypertension. 2019;74(2):359-367. DOI:10.1161/HYPERTENSIONAHA.119.12944.Burrello J, Tetti M, Forestiero V, et al. Characterization of circulating extracellular vesicle surface antigens in patients with primary aldosteronism. Hypertension. 2021;78(3):726-737. DOI:10.1161/ HYPERTENSIONAHA.121.17136.Burrello J, Tetti M, Forestiero V, et al. Characterization of circulating extracellular vesicle surface antigens in patients with primary aldosteronism. Hypertension. 2021;78(3):726-737. DOI:10.1161/ HYPERTENSIONAHA.121.17136.Parksook WW, Williams GH. Aldosterone and cardiovascular diseases. Cardiovasc Res. 2023;119(1):28-44. DOI:10.1093/cvr/cvac027.Parksook WW, Williams GH. Aldosterone and cardiovascular diseases. Cardiovasc Res. 2023;119(1):28-44. DOI:10.1093/cvr/cvac027.Le Loan TY, Mardini M, Howell VM, et al. Low-dose spironolactone prevents apoptosis repressor with caspase recruitment domain degradation during myocardial infarction. Hypertension. 2012;59(6):1164-1169. DOI:10.1161/ HYPERTENSIONAHA.111.190488.Le Loan TY, Mardini M, Howell VM, et al. Low-dose spironolactone prevents apoptosis repressor with caspase recruitment domain degradation during myocardial infarction. Hypertension. 2012;59(6):1164-1169. DOI:10.1161/ HYPERTENSIONAHA.111.190488.Mihailidou AS, Le TYL, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension. 2009;54(6):1306-1312. DOI:10.1161/HYPERTENSIONAHA.109. 136242.Mihailidou AS, Le TYL, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension. 2009;54(6):1306-1312. DOI:10.1161/HYPERTENSIONAHA.109. 136242.Funder JW. Primary aldosteronism and salt. Pflugers Arch. 2015;467(3):587-594. DOI:10.1007/s00424-014-1658-0.Funder JW. Primary aldosteronism and salt. Pflugers Arch. 2015;467(3):587-594. DOI:10.1007/s00424-014-1658-0.Hung CS, Chang YY, Tsai CH, et al. Aldosterone suppresses cardiac mitochondria. Transl Res. 2022;239:58-70. DOI:10.1016/j.trsl.2021.08.003.Hung CS, Chang YY, Tsai CH, et al. Aldosterone suppresses cardiac mitochondria. Transl Res. 2022;239:58-70. DOI:10.1016/j.trsl.2021.08.003.Williams JS, Williams GH, Raji A, et al. Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia. J Hum Hypertens. 2006;20(2):129-136. DOI:10.1038/sj.jhh.1001948.Williams JS, Williams GH, Raji A, et al. Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia. J Hum Hypertens. 2006;20(2):129-136. DOI:10.1038/sj.jhh.1001948.Catena C, Colussi G, Novello M, et al. Dietary salt intake is a determinant of cardiac changes after treatment of primary aldosteronism: a prospective study. Hypertension. 2016;68(1):204-212. DOI:10.1161/HYPERTENSIONAHA.116.07615.Catena C, Colussi G, Novello M, et al. Dietary salt intake is a determinant of cardiac changes after treatment of primary aldosteronism: a prospective study. Hypertension. 2016;68(1):204-212. DOI:10.1161/HYPERTENSIONAHA.116.07615.Chang YY, Liao CW, Tsai CH, et al. Left Ventricular Dysfunction in Patients With Primary Aldosteronism: A Propensity Score-Matching Follow-Up Study With Tissue Doppler Imaging. J Am Heart Assoc. 2019;8(22):e013263. DOI:10.1161/ JAHA.119.013263.Chang YY, Liao CW, Tsai CH, et al. Left Ventricular Dysfunction in Patients With Primary Aldosteronism: A Propensity Score-Matching Follow-Up Study With Tissue Doppler Imaging. J Am Heart Assoc. 2019;8(22):e013263. DOI:10.1161/ JAHA.119.013263.Verma A, Vaidya A, Subudhi S, Waikar SS. Aldosterone in chronic kidney disease and renal outcomes. Eur Heart J. 2022;43(38):3781-3791. DOI:10.1093/eurheartj/ ehac352.Verma A, Vaidya A, Subudhi S, Waikar SS. Aldosterone in chronic kidney disease and renal outcomes. Eur Heart J. 2022;43(38):3781-3791. DOI:10.1093/eurheartj/ ehac352.Rossing P, Filippatos G, Agarwal R, et al; FIDELIO-DKD Investigators. Finerenone in Predominantly Advanced CKD and Type 2 Diabetes With or Without Sodium Glucose Cotransporter-2 Inhibitor Therapy. Kidney Int Rep. 2021;7(1):36-45. DOI:10.1016/j.ekir.2021.10.008.Rossing P, Filippatos G, Agarwal R, et al; FIDELIO-DKD Investigators. Finerenone in Predominantly Advanced CKD and Type 2 Diabetes With or Without Sodium Glucose Cotransporter-2 Inhibitor Therapy. Kidney Int Rep. 2021;7(1):36-45. DOI:10.1016/j.ekir.2021.10.008.Pitt B, Filippatos G, Agarwal R, et al; FIGARO-DKD Investigators. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med. 2021;385(24):2252-2263. DOI:10.1056/NEJMoa2110956.Pitt B, Filippatos G, Agarwal R, et al; FIGARO-DKD Investigators. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med. 2021;385(24):2252-2263. DOI:10.1056/NEJMoa2110956.Hasegawa T, Nishiwaki H, Ota E, et al. Aldosterone antagonists for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2021;2(2):CD013109. DOI:10.1002/14651858.CD013109.pub2.Hasegawa T, Nishiwaki H, Ota E, et al. Aldosterone antagonists for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2021;2(2):CD013109. DOI:10.1002/14651858.CD013109.pub2.Agarwal R, Rossignol P, Budden J, et al. Patiromer and Spironolactone in Resistant Hypertension and Advanced CKD: Analysis of the Randomized AMBER Trial. Kidney360. 2021;2(3):425-434. DOI:10.34067/KID.0006782020.Agarwal R, Rossignol P, Budden J, et al. Patiromer and Spironolactone in Resistant Hypertension and Advanced CKD: Analysis of the Randomized AMBER Trial. Kidney360. 2021;2(3):425-434. DOI:10.34067/KID.0006782020.Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45(1):3-17.Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45(1):3-17.Conn JW. Aldosterone in clinical medicine; past, present, and future. AMA Arch Intern Med. 1956; 97(2):135-144.Conn JW. Aldosterone in clinical medicine; past, present, and future. AMA Arch Intern Med. 1956; 97(2):135-144.Conn JW. Plasma renin activity in primary aldosteronism. importance in differential diagnosis and in research of essential hypertension. JAMA. 1964;190:222-225.Conn JW. Plasma renin activity in primary aldosteronism. importance in differential diagnosis and in research of essential hypertension. JAMA. 1964;190:222-225.Ross EJ. Aldosterone and aldosteronism. London: Lloyd-Luke,1975.Ross EJ. Aldosterone and aldosteronism. London: Lloyd-Luke,1975.Conn JW, Rovner DR, Cohen EL. Normal and Altered Function of the ReninAngiotensin-Aldosterone System in Man: Applications in Clinical and Research Medicine. Ann Intern Med. 1965;63:266-284. DOI:10.7326/0003-4819-63-2-266.Conn JW, Rovner DR, Cohen EL. Normal and Altered Function of the ReninAngiotensin-Aldosterone System in Man: Applications in Clinical and Research Medicine. Ann Intern Med. 1965;63:266-284. DOI:10.7326/0003-4819-63-2-266.Carey RM, Wright JT, Taler SJ, Whelton PK. Guideline-Driven Management of Hypertension: An Evidence-Based Update. Circ Res. 2021;128(7):827-846. DOI:10.1161/CIRCRESAHA.121.318083.Carey RM, Wright JT, Taler SJ, Whelton PK. Guideline-Driven Management of Hypertension: An Evidence-Based Update. Circ Res. 2021;128(7):827-846. DOI:10.1161/CIRCRESAHA.121.318083.Brown JM, Siddiqui M, Calhoun DA, et al. The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study. Ann Intern Med. 2020;173(1):10- 20. DOI:10.7326/M20-0065.Brown JM, Siddiqui M, Calhoun DA, et al. The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study. Ann Intern Med. 2020;173(1):10- 20. DOI:10.7326/M20-0065.Cohen JB, Cohen DL, Herman DS, et al. Testing for Primary Aldosteronism and Mineralocorticoid Receptor Antagonist Use Among U. S. Veterans: A Retrospective Cohort Study. Ann Intern Med. 2021;174(3):289-297. DOI:10.7326/ M20-4873.Cohen JB, Cohen DL, Herman DS, et al. Testing for Primary Aldosteronism and Mineralocorticoid Receptor Antagonist Use Among U. S. Veterans: A Retrospective Cohort Study. Ann Intern Med. 2021;174(3):289-297. DOI:10.7326/ M20-4873.Williams B, MacDonald TM, Morant S, et al; 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;386(10008):2059-2068. DOI:10.1016/S0140-6736(15)00257-3.Williams B, MacDonald TM, Morant S, et al; 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;386(10008):2059-2068. DOI:10.1016/S0140-6736(15)00257-3.Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. DOI:10.1210/jc.2015-4061.Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. DOI:10.1210/jc.2015-4061.Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. A systematic review of the literature. Endocrinol Metab Clin North Am. 2002;31(3):619-632, xi. DOI:10.1016/s0889-8529(02)00013-0.Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. A systematic review of the literature. Endocrinol Metab Clin North Am. 2002;31(3):619-632, xi. DOI:10.1016/s0889-8529(02)00013-0.Ariens J, Horvath AR, Yang J, Choy KW. Performance of the aldosterone-to-renin ratio as a screening test for primary aldosteronism in primary care. Endocrine. 2022;77(1):11-20. DOI:10.1007/s12020-022-03084-x.Ariens J, Horvath AR, Yang J, Choy KW. Performance of the aldosterone-to-renin ratio as a screening test for primary aldosteronism in primary care. Endocrine. 2022;77(1):11-20. DOI:10.1007/s12020-022-03084-x.Tsujimoto T, Kajio H. Spironolactone Use and Improved Outcomes in Patients With Heart Failure With Preserved Ejection Fraction With Resistant Hypertension. J Am Heart Assoc. 2020;9(23):e018827. DOI:10.1161/JAHA.120.018827.Tsujimoto T, Kajio H. Spironolactone Use and Improved Outcomes in Patients With Heart Failure With Preserved Ejection Fraction With Resistant Hypertension. J Am Heart Assoc. 2020;9(23):e018827. DOI:10.1161/JAHA.120.018827.Hasegawa T, Masugi F, Ogihara T, Kumahara Y. Increase in plasma ouabainlike inhibitor of Na+, K+−ATPase with high sodium intake in patients with essential hypertension. J Clin Hypertens. 1987;3(4):419-429.Hasegawa T, Masugi F, Ogihara T, Kumahara Y. Increase in plasma ouabainlike inhibitor of Na+, K+−ATPase with high sodium intake in patients with essential hypertension. J Clin Hypertens. 1987;3(4):419-429.Laredo J, Shah JR, Lu ZR, et al. Angiotensin II stimulates secretion of endogenous ouabain from bovine adrenocortical cells via angiotensin type 2 receptors. Hypertension. 1997;29(1 Pt 2):401-407. DOI:10.1161/01.hyp.29.1.401.Laredo J, Shah JR, Lu ZR, et al. Angiotensin II stimulates secretion of endogenous ouabain from bovine adrenocortical cells via angiotensin type 2 receptors. Hypertension. 1997;29(1 Pt 2):401-407. DOI:10.1161/01.hyp.29.1.401.Rossi GP, Belfiore A, Bernini G, et al. Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients. J Clin Endocrinol Metab. 2008;93(7):2566-2571. DOI:10.1210/jc.2008-0251.Rossi GP, Belfiore A, Bernini G, et al. Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients. J Clin Endocrinol Metab. 2008;93(7):2566-2571. DOI:10.1210/jc.2008-0251.Acelajado MC, Pimenta E, Calhoun DA. Salt and aldosterone: a concert of bad ef - fects. Hypertension. 2010;56(5):804-805. DOI:10.1161/HYPERTENSIONAHA.110. 160960.Acelajado MC, Pimenta E, Calhoun DA. Salt and aldosterone: a concert of bad ef - fects. Hypertension. 2010;56(5):804-805. DOI:10.1161/HYPERTENSIONAHA.110. 160960.Neal B, Wu Y, Feng X, et al. Effect of Salt Substitution on Cardiovascular Events and Death. N Engl J Med. 2021;385(12):1067-1077. DOI:10.1056/NEJMoa2105675.Neal B, Wu Y, Feng X, et al. Effect of Salt Substitution on Cardiovascular Events and Death. N Engl J Med. 2021;385(12):1067-1077. DOI:10.1056/NEJMoa2105675.Gaddam K, Corros C, Pimenta E, et al. Rapid reversal of left ventricular hypertrophy and intracardiac volume overload in patients with resistant hypertension and hyperaldosteronism: a prospective clinical study. Hypertension. 2010;55(5):1137- 1142. DOI:10.1161/HYPERTENSIONAHA.109.141531.Gaddam K, Corros C, Pimenta E, et al. Rapid reversal of left ventricular hypertrophy and intracardiac volume overload in patients with resistant hypertension and hyperaldosteronism: a prospective clinical study. Hypertension. 2010;55(5):1137- 1142. DOI:10.1161/HYPERTENSIONAHA.109.141531.Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008;168(11):1159- 1164. DOI:10.1001/archinte.168.11.1159.Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008;168(11):1159- 1164. DOI:10.1001/archinte.168.11.1159.Williams B, Mancia G, Spiering W, et al; ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104. DOI:10.1093/eurheartj/ehy339.Williams B, Mancia G, Spiering W, et al; ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104. DOI:10.1093/eurheartj/ehy339.Liu L, Xu B, Ju Y. Addition of spironolactone in patients with resistant hypertension: A meta-analysis of randomized controlled trials. Clin Exp Hypertens. 2017;39(3):257-263. DOI:10.1080/10641963.2016.1246564.Liu L, Xu B, Ju Y. Addition of spironolactone in patients with resistant hypertension: A meta-analysis of randomized controlled trials. Clin Exp Hypertens. 2017;39(3):257-263. DOI:10.1080/10641963.2016.1246564.Freeman MW, Halvorsen YD, Marshall W, et al; BrigHTN Investigators. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. 2023;388(5):395-405. DOI:10.1056/NEJMoa2213169.Freeman MW, Halvorsen YD, Marshall W, et al; BrigHTN Investigators. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. 2023;388(5):395-405. DOI:10.1056/NEJMoa2213169.Nanba K, Vaidya A, Williams GH, et al. Age-Related Autonomous Aldosteronism. Circulation. 2017;136(4):347-355. DOI:10.1161/CIRCULATIONAHA.117.028201.Nanba K, Vaidya A, Williams GH, et al. Age-Related Autonomous Aldosteronism. Circulation. 2017;136(4):347-355. DOI:10.1161/CIRCULATIONAHA.117.028201.

The authors declare that there are no conflicts of interest present.