Download PDF
CC BY-NC-ND 4.0 · Horm Metab Res 2020; 52(06): 386-393
DOI: 10.1055/a-1116-2407
Review

Salt Appetite and its Effects on Cardiovascular Risk in Primary Aldosteronism

Christian Adolf
1   Medizinische Klinik und Poliklinik IV, LMU München, Munich, Germany
,
Holger Schneider
1   Medizinische Klinik und Poliklinik IV, LMU München, Munich, Germany
,
Daniel A. Heinrich
1   Medizinische Klinik und Poliklinik IV, LMU München, Munich, Germany
,
Laura Handgriff
1   Medizinische Klinik und Poliklinik IV, LMU München, Munich, Germany
,
Martin Reincke
1   Medizinische Klinik und Poliklinik IV, LMU München, Munich, Germany
› Author Affiliations Funding Information: This work was supported by the Else Kröner-Fresenius Stiftung in support of the German Conn’s Registry-Else-Kröner Hyperaldosteronism Registry (2013_A182 and 2015_A171 to MR), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 694913 to MR), by the Deutsche Forschungsgemeinschaft (DFG) (within the CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease” to CA, DAH, HS and MR).
› Further Information
Also available at
    Permissions and Reprints

Abstract

First described in 1955 by Jerome W. Conn, primary aldosteronism (PA) today is well established as a relevant cause of secondary hypertension and accounts for about 5–10 % of hypertensives. The importance of considering PA is based on its deleterious target organ damage far beyond the effect of elevated blood pressure and on PA being a potentially curable form of hypertension. Aside the established contributory role of high dietary salt intake to arterial hypertension and cardiovascular disease, high salt intake is mandatory for aldosterone-mediated deleterious effects on target-organ damage in patients with primary aldosteronism. Consequently, counselling patients on the need to reduce salt intake represents a major component in the treatment of PA to minimize cardiovascular damage. Unfortunately, in PA patients salt intake is high and far beyond the target values of 5 g per day, recommended by the World Health Organization. Insufficient patient motivation for lifestyle interventions can be further complicated by enhancing effects of aldosterone on salt appetite, via central and gustatory pathways. In this context, treatment for PA by adrenalectomy results in a spontaneous decrease in dietary salt intake and might therefore provide further reduction of cardiovascular risk in PA than specific medical treatment alone. Furthermore, there is evidence from clinical studies that even after sufficient treatment of PA dietary salt intake remains a relevant prognostic factor for cardiovascular risk. This review will focus on the synergistic benefits derived from both blockade of aldosterone-mediated effects and reduction in dietary salt intake on cardiovascular risk.

Key words

salt intake - oxidative stress - aldosterone


Publication History

Received: 06 December 2019

Accepted: 28 January 2020

Article published online:
06 April 2020

© 2020. Thieme. All rights reserved.

© Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Cook NR, Appel LJ, Whelton PK. Lower levels of sodium intake and reduced cardiovascular risk. Circulation 2014; 129: 981-989
    CrossrefPubMedGoogle Scholar
  • 2 Cook NR, Appel LJ, Whelton PK. Sodium intake and all-cause mortality over 20 years in the trials of hypertension prevention. J Am Coll Cardiol 2016; 68: 1609-1617
    CrossrefPubMedGoogle Scholar
  • 3 Mills KT, Chen J, Yang W. et al. Sodium excretion and the risk of cardiovascular disease in patients with chronic kidney disease. JAMA 2016; 315: 2200-2210
    CrossrefPubMedGoogle Scholar
  • 4 He FJ, MacGregor GA. Salt reduction lowers cardiovascular risk: Meta-analysis of outcome trials. Lancet 2011; 378: 380-382
    CrossrefPubMedGoogle Scholar
  • 5 Williams B, Mancia G, Spiering W. et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018; 39: 3021-3104
    CrossrefPubMedGoogle Scholar
  • 6 [Anonymous] Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser 2003; 916 i–viii. 1-149 backcover
    PubMedGoogle Scholar
  • 7 Powles J, Fahimi S, Micha R. et al. Global, regional and national sodium intakes in 1990 and 2010: A systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide. BMJ Open 2013; 3: e003733
    CrossrefPubMedGoogle Scholar
  • 8 Brown IJ, Tzoulaki I, Candeias V. et al. Salt intakes around the world: Implications for public health. Int J Epidemiol 2009; 38: 791-813
    CrossrefPubMedGoogle Scholar
  • 9 Mattes RD, Donnelly D. Relative contributions of dietary sodium sources. J Am Coll Nutr 1991; 10: 383-393
    CrossrefPubMedGoogle Scholar
  • 10 He FJ, MacGregor GA. A comprehensive review on salt and health and current experience of worldwide salt reduction programmes. J Hum Hypertens 2009; 23: 363-384
    CrossrefPubMedGoogle Scholar
  • 11 Milliez P, Girerd X, Plouin PF. et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45: 1243-1248
    CrossrefPubMedGoogle Scholar
  • 12 Monticone S, D'Ascenzo F, Moretti C. et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: A systematic review and meta-analysis. Lancet Diabetes Endocrinol 2018; 6: 41-50
    CrossrefPubMedGoogle Scholar
  • 13 Monticone S, Burrello J, Tizzani D. et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol 2017; 69: 1811-1820
    PubMedGoogle Scholar
  • 14 Rossi GP, Bernini G, Caliumi C. et al. A prospective study of the prevalence of primary aldosteronism in 1125 hypertensive patients. J Am Coll Cardiol 2006; 48: 2293-2300
    CrossrefPubMedGoogle Scholar
  • 15 Rocha R, Rudolph AE, Frierdich GE. et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2002; 283: H1802-H1810
    CrossrefPubMedGoogle Scholar
  • 16 Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 1992; 120: 893-901
    Google Scholar
  • 17 Young M, Fullerton M, Dilley R. et al. Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest 1994; 93: 2578-2583
    CrossrefPubMedGoogle Scholar
  • 18 Rocha R, Stier CT, Kifor I. et al. Aldosterone: A mediator of myocardial necrosis and renal arteriopathy. Endocrinology 2000; 141: 3871-3878
    CrossrefPubMedGoogle Scholar
  • 19 Mente A, O'Donnell MJ, Rangarajan S. et al. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med 2014; 371: 601-611
    CrossrefPubMedGoogle Scholar
  • 20 O'Donnell M, Mente A, Rangarajan S. et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014; 371: 612-623
    CrossrefPubMedGoogle Scholar
  • 21 Cappuccio FP, Beer M, Strazzullo P. et al. Population dietary salt reduction and the risk of cardiovascular disease. A scientific statement from the European Salt Action Network. Nutr Metab Cardiovasc Dis 2018; 29: 107-114
    PubMedGoogle Scholar
  • 22 Holbrook JT, Patterson KY, Bodner JE. Sodium and potassium intake and balance in adults consuming self-selected diets. Am J Clin Nutr 1984; 40: 786-793
    CrossrefPubMedGoogle Scholar
  • 23 Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med 1985; 312: 283-289
    CrossrefPubMedGoogle Scholar
  • 24 Meneton P, Jeunemaitre X, de Wardener HE. et al. Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiol Rev 2005; 85: 679-715
    CrossrefPubMedGoogle Scholar
  • 25 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: 204-212
    CrossrefPubMedGoogle Scholar
  • 26 Pimenta E, Gordon RD, Ahmed AH. et al. Unilateral adrenalectomy improves urinary protein excretion but does not abolish its relationship to sodium excretion in patients with aldosterone-producing adenoma. J Hum Hypertens 2011; 25: 592-599
    CrossrefPubMedGoogle Scholar
  • 27 Hung CS, Wu XM, Chen CW. et al. The relationship among cardiac structure, dietary salt and aldosterone in patients with primary aldosteronism. Oncotarget 2017; 8: 73187-73197
    CrossrefPubMedGoogle Scholar
  • 28 Pimenta E, Gordon RD, Ahmed AH. et al. Cardiac dimensions are largely determined by dietary salt in patients with primary aldosteronism: Results of a case-control study. J Clin Endocrinol Metab 2011; 96: 2813-2820
    CrossrefPubMedGoogle Scholar
  • 29 Adolf C, Heinrich DA, Holler F. et al. Patients with primary aldosteronism respond to unilateral adrenalectomy with long-term reduction in salt intake. J Clin Endocrinol Metab. 2019 DOI: 10.1210/clinem/dgz051
    PubMedGoogle Scholar
  • 30 Johner SA, Thamm M, Schmitz R. et al. Current daily salt intake in Germany: Biomarker-based analysis of the representative DEGS study. Eur J Nutr 2015; 54: 1109-1115
    CrossrefPubMedGoogle Scholar
  • 31 Makhanova N, Sequeira-Lopez ML, Gomez RA. et al. Disturbed homeostasis in sodium-restricted mice heterozygous and homozygous for aldosterone synthase gene disruption. Hypertension 2006; 48: 1151-1159
    CrossrefPubMedGoogle Scholar
  • 32 Wolf G. Effect of deoxycorticosterone on sodium appetite of intact and adrenalectomized rats. Am J Physiol 1965; 208: 1281-1285
    PubMedGoogle Scholar
  • 33 Weisinger RS, Woods SC. Aldosterone-elicited sodium appetite. Endocrinology 1971; 89: 538-544
    CrossrefPubMedGoogle Scholar
  • 34 Geerling JC, Loewy AD. Aldosterone-sensitive NTS neurons are inhibited by saline ingestion during chronic mineralocorticoid treatment. Brain Res 2006; 1115: 54-64
    CrossrefPubMedGoogle Scholar
  • 35 Vinson GP. The mislabelling of deoxycorticosterone: Making sense of corticosteroid structure and function. The Journal of endocrinology 2011; 211: 3-16
    CrossrefPubMedGoogle Scholar
  • 36 Wolf G, Handal PJ. Aldosterone-induced sodium appetite: Dose-response and specificity. Endocrinology 1966; 78: 1120-1124
    CrossrefPubMedGoogle Scholar
  • 37 Formenti S, Bassi M, Nakamura NB. et al. Hindbrain mineralocorticoid mechanisms on sodium appetite. Am J Physiol Regul Integr Comp Physiol 2013; 304: R252-R259
    CrossrefPubMedGoogle Scholar
  • 38 Sakai RR, McEwen BS, Fluharty SJ. et al. The amygdala: Site of genomic and nongenomic arousal of aldosterone-induced sodium intake. Kidney Int 2000; 57: 1337-1345
    CrossrefPubMedGoogle Scholar
  • 39 Vallon V, Huang DY, Grahammer F. et al. SGK1 as a determinant of kidney function and salt intake in response to mineralocorticoid excess. Am J Physiol Regul Integr Comp Physiol 2005; 289: R395-R401
    CrossrefPubMedGoogle Scholar
  • 40 Francis J, Weiss RM, Wei SG. et al. Central mineralocorticoid receptor blockade improves volume regulation and reduces sympathetic drive in heart failure. Am J Physiol Heart Circ Physiol 2001; 281: H2241-H2251
    CrossrefPubMedGoogle Scholar
  • 41 Leshem M, Abutbul A, Eilon R. Exercise increases the preference for salt in humans. Appetite 1999; 32: 251-260
    CrossrefPubMedGoogle Scholar
  • 42 Fu Y, Vallon V. Mineralocorticoid-induced sodium appetite and renal salt retention: Evidence for common signaling and effector mechanisms. Nephron Physiol 2014; 128: 8-16
    CrossrefPubMedGoogle Scholar
  • 43 Murck H. Aldosterone Action on Brain and Behavior. In: 2017; 159-179
    PubMed
  • 44 Funder JW. Glucocorticoid and mineralocorticoid receptors: Biology and clinical relevance. Annu Rev Med 1997; 48: 231-240
    CrossrefPubMedGoogle Scholar
  • 45 Roland BL, Li KX, Funder JW. Hybridization histochemical localization of 11 beta-hydroxysteroid dehydrogenase type 2 in rat brain. Endocrinology 1995; 136: 4697-4700
    CrossrefPubMedGoogle Scholar
  • 46 Qiao H, Hu B, Zhou H. et al. Aldosterone induces rapid sodium intake by a nongenomic mechanism in the nucleus tractus solitarius. Sci Rep 2016; 6: 38631
    CrossrefPubMedGoogle Scholar
  • 47 Koneru B, Bathina CS, Cherry BH. et al. Mineralocorticoid receptor in the NTS stimulates saline intake during fourth ventricular infusions of aldosterone. Am J Physiol Regul Integr Comp Physiol 2014; 306: R61-R66
    CrossrefPubMedGoogle Scholar
  • 48 Evans LC, Ivy JR, Wyrwoll C. et al. Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension. Circulation 2016; 133: 1360-1370
    CrossrefPubMedGoogle Scholar
  • 49 Robson AC, Leckie CM, Seckl JR. et al. 11 Beta-hydroxysteroid dehydrogenase type 2 in the postnatal and adult rat brain. Brain Res Mol Brain Res 1998; 61: 1-10
    CrossrefPubMedGoogle Scholar
  • 50 Zhang ZH, Kang YM, Yu Y. et al. 11beta-hydroxysteroid dehydrogenase type 2 activity in hypothalamic paraventricular nucleus modulates sympathetic excitation. Hypertension 2006; 48: 127-133
    CrossrefPubMedGoogle Scholar
  • 51 Geerling JC, Loewy AD. Central regulation of sodium appetite. Experimental physiology 2008; 93: 177-209
    CrossrefPubMedGoogle Scholar
  • 52 Krause EG, Sakai RR. Richter and sodium appetite: From adrenalectomy to molecular biology. Appetite 2007; 49: 353-367
    CrossrefPubMedGoogle Scholar
  • 53 Chandrashekar J, Kuhn C, Oka Y. et al. The cells and peripheral representation of sodium taste in mice. Nature 2010; 464: 297-301
    PubMedGoogle Scholar
  • 54 Sakamoto T, Fujii A, Saito N. et al. Alteration of amiloride-sensitive salt taste nerve responses in aldosterone/NaCl-induced hypertensive rats. Neurosci Res 2016; 108: 60-66
    CrossrefPubMedGoogle Scholar
  • 55 Adolf C, Görge V, Heinrich D. et al. P01–06: Taste perception of salt in patients with primary aldosteronism. In. 61. Deutscher Kongress für Endokrinologie. 2018 2018.
    PubMedGoogle Scholar
  • 56 Blasi ER, Rocha R, Rudolph AE. et al. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int 2003; 63: 1791-1800
    CrossrefPubMedGoogle Scholar
  • 57 Martinez DV, Rocha R, Matsumura M. et al. Cardiac damage prevention by eplerenone: Comparison with low sodium diet or potassium loading. Hypertension 2002; 39: 614-618
    CrossrefPubMedGoogle Scholar
  • 58 Funder JW. Primary aldosteronism and salt. Pflugers Arch 2015; 467: 587-594
    CrossrefPubMedGoogle Scholar
  • 59 Gomez-Sanchez EP, Venkataraman MT, Thwaites D. et al. ICV infusion of corticosterone antagonizes ICV-aldosterone hypertension. Am J Physiol 1990; 258: E649-E653
    PubMedGoogle Scholar
  • 60 Stowasser M, Sharman J, Leano R. et al. Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I. J Clin Endocrinol Metab 2005; 90: 5070-5076
    CrossrefPubMedGoogle Scholar
  • 61 du Cailar G, Mimran A, Fesler P. et al. Dietary sodium and pulse pressure in normotensive and essential hypertensive subjects. J Hypertens 2004; 22: 697-703
    CrossrefPubMedGoogle Scholar
  • 62 du Cailar G, Ribstein J, Mimran A. Dietary sodium and target organ damage in essential hypertension. Am J Hypertens 2002; 15: 222-229
    CrossrefPubMedGoogle Scholar
  • 63 Kusche-Vihrog K, Schmitz B, Brand E. Salt controls endothelial and vascular phenotype. Pflugers Arch 2015; 467: 499-512
    CrossrefPubMedGoogle Scholar
  • 64 Gonzalez M, Lobos L, Castillo F. et al. High-salt diet inhibits expression of angiotensin type 2 receptor in resistance arteries. Hypertension 2005; 45: 853-859
    CrossrefPubMedGoogle Scholar
  • 65 Nickenig G, Strehlow K, Roeling J. et al. Salt induces vascular AT1 receptor overexpression in vitro and in vivo. Hypertension 1998; 31: 1272-1277
    CrossrefPubMedGoogle Scholar
  • 66 Takeda Y, Yoneda T, Demura M. et al. Sodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy. Endocrinology 2000; 141: 1901-1904
    CrossrefPubMedGoogle Scholar
  • 67 Gomez-Sanchez EP, Ahmad N, Romero DG. et al. Origin of aldosterone in the rat heart. Endocrinology 2004; 145: 4796-4802
    CrossrefPubMedGoogle Scholar
  • 68 Ye P, Kenyon CJ, MacKenzie SM. et al. The aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) genes are not expressed in the rat heart. Endocrinology 2005; 146: 5287-5293
    CrossrefPubMedGoogle Scholar
  • 69 Tentori S, Messaggio E, Brioni E. et al. Endogenous ouabain and aldosterone are coelevated in the circulation of patients with essential hypertension. J Hypertens 2016; 34: 2074-2080
    CrossrefPubMedGoogle Scholar
  • 70 Manunta P, Hamilton BP, Hamlyn JM. Salt intake and depletion increase circulating levels of endogenous ouabain in normal men. Am J Physiol Regul Integr Comp Physiol 2006; 290: R553-R559
    CrossrefPubMedGoogle Scholar
  • 71 Kaaja RJ, Nicholls MG. Does the hormone "endogenous ouabain" exist in the human circulation?. Biofactors 2018; 44: 219-221
    CrossrefPubMedGoogle Scholar
  • 72 Baecher S, Kroiss M, Fassnacht M. et al. No endogenous ouabain is detectable in human plasma by ultra-sensitive UPLC-MS/MS. Clin Chim Acta 2014; 431: 87-92
    CrossrefPubMedGoogle Scholar
  • 73 Yu HC, Burrell LM, Black MJ. Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats. Circulation 1998; 98: 2621-2628
    CrossrefPubMedGoogle Scholar
  • 74 Schnackenberg CG, Wilcox CS. Two-week administration of tempol attenuates both hypertension and renal excretion of 8-Iso prostaglandin f2alpha. Hypertension 1999; 33: 424-428
    CrossrefPubMedGoogle Scholar
  • 75 Roberts LJ, Morrow JD. The generation and actions of isoprostanes. Biochim Biophys Acta 1997; 1345: 121-135
    CrossrefPubMedGoogle Scholar
  • 76 Laffer CL, Bolterman RJ, Romero JC. Effect of salt on isoprostanes in salt-sensitive essential hypertension. Hypertension 2006; 47: 434-440
    CrossrefPubMedGoogle Scholar
  • 77 Meng S, Roberts LJ, Cason GW. Superoxide dismutase and oxidative stress in Dahl salt-sensitive and -resistant rats. Am J Physiol Regul Integr Comp Physiol 2002; 283: R732-R738
    CrossrefPubMedGoogle Scholar
  • 78 Kitiyakara C, Chabrashvili T, Chen Y. et al. Salt intake, oxidative stress, and renal expression of NADPH oxidase and superoxide dismutase. J Am Soc Nephrol 2003; 14: 2775-2782
    CrossrefPubMedGoogle Scholar
  • 79 Wilck N, Matus MG, Kearney SM. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 2017; 551: 585-589
    CrossrefPubMedGoogle Scholar
  • 80 Mell B, Jala VR, Mathew AV. et al. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol Genomics 2015; 47: 187-197
    CrossrefPubMedGoogle Scholar
  • 81 Durgan DJ, Ganesh BP, Cope JL. et al. Role of the Gut Microbiome in Obstructive Sleep Apnea-Induced Hypertension. Hypertension 2016; 67: 469-474
    CrossrefPubMedGoogle Scholar
  • 82 Yang T, Santisteban MM, Rodriguez V. et al. Gut dysbiosis is linked to hypertension. Hypertension 2015; 65: 1331-1340
    CrossrefPubMedGoogle Scholar
  • 83 Agus A, Denizot J, Thevenot J. et al. Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent-Invasive E. coli infection and intestinal inflammation. Sci Rep 2016; 6: 19032
    CrossrefPubMedGoogle Scholar
  • 84 Kim S, Goel R, Kumar A. et al. Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure. Clin Sci (Lond) 2018; 132: 701-718
    CrossrefPubMedGoogle Scholar
  • 85 Toral M, Robles-Vera I, de la Visitacion N. et al. Role of the immune system in vascular function and blood pressure control induced by faecal microbiota transplantation in rats. Acta Physiol (Oxf) 2019; 227: e13285
    PubMedGoogle Scholar
  • 86 Yi B, Titze J, Rykova M. et al. Effects of dietary salt levels on monocytic cells and immune responses in healthy human subjects: A longitudinal study. Transl Res 2015; 166: 103-110
    CrossrefPubMedGoogle Scholar
  • 87 Wang C, Huang Z, Yu K. et al. High-salt diet has a certain impact on protein digestion and gut microbiota: A sequencing and proteome combined study. Front Microbiol 2017; 8: 1838
    CrossrefPubMedGoogle Scholar
  • 88 Miranda PM, De Palma G, Serkis V. et al. High salt diet exacerbates colitis in mice by decreasing Lactobacillus levels and butyrate production. Microbiome 2018; 6: 57
    CrossrefPubMedGoogle Scholar
  • 89 Ferguson JF, Aden LA, Barbaro NR. et al. High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension. JCI Insight 2019; 5 DOI: 10.1172/jci.insight.126241.
    CrossrefPubMedGoogle Scholar
  • 90 Lukens JR, Gurung P, Vogel P. et al. Dietary modulation of the microbiome affects autoinflammatory disease. Nature 2014; 516: 246-249
    PubMedGoogle Scholar
  • 91 Scher JU, Sczesnak A, Longman RS. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2013; 2: e01202
    CrossrefPubMedGoogle Scholar
  • 92 Herrada AA, Contreras FJ, Marini NP. et al. Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity. J Immunol 2010; 184: 191-202
    CrossrefPubMedGoogle Scholar
  • 93 Amador CA, Barrientos V, Pena J. et al. Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes. Hypertension 2014; 63: 797-803
    CrossrefPubMedGoogle Scholar
  • 94 Edwards CR, Stewart PM, Burt D. et al. Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor. Lancet 1988; 2: 986-989
    PubMedGoogle Scholar
  • 95 Funder JW, Pearce PT, Smith R. et al. Mineralocorticoid action: Target tissue specificity is enzyme, not receptor, mediated. Science 1988; 242: 583-585
    CrossrefPubMedGoogle Scholar
  • 96 Funder JW. RALES, EPHESUS and redox. J Steroid Biochem Mol Biol 2005; 93: 121-125
    CrossrefPubMedGoogle Scholar
  • 97 Mihailidou AS, Loan LeTY, Mardini M. et al. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension 2009; 54: 1306-1312
    CrossrefPubMedGoogle Scholar
  • 98 Callera GE, Touyz RM, Tostes RC. et al. Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension 2005; 45: 773-779
    CrossrefPubMedGoogle Scholar
  • 99 Keidar S, Kaplan M, Pavlotzky E. et al. Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: A possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation 2004; 109: 2213-2220
    CrossrefPubMedGoogle Scholar
  • 100 Arlt W, Lang K, Sitch AJ. et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight. 2017 2. DOI: 10.1172/jci.insight.93136
    PubMedGoogle Scholar
  • 101 Spath M, Korovkin S, Antke C. et al. Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism. Eur J Endocrinol 2011; 164: 447-455
    CrossrefPubMedGoogle Scholar
  • 102 Yoon V, Heyliger A, Maekawa T. et al. Benign adrenal adenomas secreting excess mineralocorticoids and glucocorticoids. Endocrinol Diabetes Metab Case Rep 2013; 2013: 130042
    PubMedGoogle Scholar
  • 103 Tong A, Liu G, Wang F. et al. A Novel phenotype of familial hyperaldosteronism type III: Concurrence of aldosteronism and cushing's syndrome. J Clin Endocrinol Metab 2016; 101: 4290-4297
    CrossrefPubMedGoogle Scholar
  • 104 Young MJ, Moussa L, Dilley R. et al. Early inflammatory responses in experimental cardiac hypertrophy and fibrosis: Effects of 11 beta-hydroxysteroid dehydrogenase inactivation. Endocrinology 2003; 144: 1121-1125
    CrossrefPubMedGoogle Scholar
  • 105 Kuster GM, Kotlyar E, Rude MK. et al. Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload. Circulation 2005; 111: 420-427
    CrossrefPubMedGoogle Scholar
  • 106 Fjeld CC, Birdsong WT, Goodman RH. Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor. Proc Natl Acad Sci USA 2003; 100: 9202-9207
    CrossrefPubMedGoogle Scholar
  • 107 Zhang Q, Piston DW, Goodman RH. Regulation of corepressor function by nuclear NADH. Science 2002; 295: 1895-1897
    PubMedGoogle Scholar
  • 108 Funder JW. Is aldosterone bad for the heart?. Trends Endocrinol Metab 2004; 15: 139-142
    CrossrefPubMedGoogle Scholar
  • 109 Hundemer GL, Curhan GC, Yozamp N. et al. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: A retrospective cohort study. Lancet Diabetes Endocrinol 2018; 6: 51-59
    CrossrefPubMedGoogle Scholar
  • 110 Funder JW. Primary aldosteronism and cardiovascular risk, before and after treatment. Lancet Diabetes Endocrinol 2018; 6: 5-7
    CrossrefPubMedGoogle Scholar
  • 111 Wessler JD, Hummel SL, Maurer MS. Dietary interventions for heart failure in older adults: re-emergence of the hedonic shift. Prog Cardiovasc Dis 2014; 57: 160-167
    CrossrefPubMedGoogle Scholar