REVISIÓN

Aldosterone: a cardiometabolic risk hormone?

Aldosterona: ¿Hormona de riesgo cardiometabólico?

Patricia Feliciano Pereira¹, Silvia Eloiza Priore² and Josefina Bressan²

¹PhD. Student of Nutrition Science, Federal University of Viçosa.
²Associate Teacher of Nutrition and Health Department, Federal University of Viçosa, Brazil.

Correspondence

ABSTRACT

Introduction: A aldosterone is a component of the renin-angiotensin-aldosterone system, classically known for its role in sodium and water retention. Besides its effects, has been shown that the aldosterone is associated with the pathogenesis and progression of metabolic syndrome components. A better understanding of this system and interfering factors could help develop pharmacotherapeutic alternatives for several disorders.
Objectives: Investigate the relationship between diet and aldosterone, and its influence on cardiometabolic risk factors.
Results and Discussion: Diet can affect plasma aldosterone levels; high fructose and fat intake can lead to increased aldosterone levels, whereas the effect of sodium intake remains controversial. Adipose tissue, particularly visceral tissue, appears to produce a lipid-soluble factor that increases aldosterone production. Patients with metabolic syndrome have higher aldosterone levels; moreover, an increased cardiometabolic risk associated with insulin resistance could be partially mediated by the action of aldosterone via mineralocorticoid receptors. Even a subtle activation of this hormonal system may have deleterious effects on the glucose and lipid metabolism related to metabolic syndrome. Nevertheless, additional studies are required to better understand the interactions among adipose tissue, aldosterone, and cardiovascular risk as well as the possible role of diet.

Key words: Aldosterone. Obesity. Metabolic syndrome. Cardiovascular diseases.

RESUMEN

Palabras clave: Aldosterona. Obesidad. Síndrome metabólico. Enfermedades cardiovasculares.

Abbreviations
BMI: Body mass index.
CI: Confidence interval.
CYP11B2: Aldosterone synthase.
HDL: High density lipoprotein cholesterol.
HF: High-fat diet. ]]> HOMA-IR: Homeostasis model assessment-estimated insulin resistance.
ICAM-1: Intercellular adhesion molecule-1.
LDL: Low density lipoprotein cholsterol.
LF: Low-fat diet.
MCP-1: Monocyte chemotactic protein-1.
mRNA: Messenger ribonucleic acid.
NAD(P)H: Nicotinamide adeninedinucleotide phosphate.
NF-κβ:Factor nuclear kappa B.
PAI-1: Plasminogen activator inhibitor-1.
PPAR-γ:Peroxisome proliferator-activated receptor. ]]> OR: Odds ratio.
RAAS: Renin-angiotensin-aldosterone system.
StAR: Steroidogenic acute regulatory protein.
TNF α: Tumor necrosis factor α.
VLDL: Very low density lipoprotein cholesterol.

Introduction

The discovery of aldosterone by Simpson et al. in 1950 had a marked effect in the field of medicine¹. At present, aldosterone is well known to play a role in electrolyte transport, wherein it promotes the increased absorption of sodium as well as excretion of potassium. Aldosterone binds to mineralocorticoid receptors on epithelial cells such as those in the kidneys as well as non-epithelial tissues including cardiomyocytes, hippocampal cells, blood vessel walls (i.e. smooth muscle and endothelial cells), and monocytes³.

Aldosterone is synthesized from cholesterol in the zona glomerulosa of the adrenal glands. However, the synthesis of aldosterone in other areas such as the heart, blood vessels, and brain has also been proposed^4-7. Aldosterone synthesis is stimulated by several factors, particularly by the lipid-soluble factor produced in adipose tissue, especially in the abdominal region^8,9.

As a component of the renin-angiotensin-aldosterone system (RAAS), aldosterone is classically known for its role in sodium and water retention¹⁰. Besides its effects on the RAAS, aldosterone is strongly associated with the pathogenesis and progression of metabolic syndrome components^11-16. In this case, aldosterone appears to promote adipogenesis and affect glucose metabolism, thus leading to insulin resistance via several mechanisms including oxidative stress, inflammation, and interference with the synthesis of enzymes involved in glucidic metabolism^9,17,18. The pro-inflammatory and prothrombotic effects of aldosterone on the cardiovascular system promote cardiac hypertrophy and remodeling; this suggests a strong etiologic association between the aldosterone pathway and the atherosclerotic process^2,10. Considering the complexity and incomplete understanding of the pathogenesis of metabolic syndrome, the objective of this review study was to critically investigate the relationship between diet and aldosterone, and the influence of this in the development and progression of cardiometabolic syndrome.

Methodology

The electronic bibliographic index (Web of Science, Science Direct, Pubmed and Scopus) and a multidisciplinary database for Ibero-America (Scielo) were searched from the earliest available online indexing year through March 2014, without language or filters restrictions. The study was conducted using the following keywords: "aldosterone" and/or "diet", "sodium intake", "obesity", "insulin resistance", "blood pressure", "dyslipidemia", "inflammation", "oxidative stress", "metabolic syndrome", "cardiometabolic syndrome", and "cardiovascular disease". Papers were selected which related to population studies and clinical trials with humans or animals, published from 2004 to 2014, as well as other relevant studies published prior to these dates.

Aldosterone and the Renin-Angiotensin System

Aldosterone is the most important mineralocorticoid that is naturally present in humans¹⁹. Even a subtle activation of the aldosterone pathway may lead to slight changes in its serum concentrations, and consequently, a quick onset of action¹⁰.

Activation by angiotensin II is the primary stimulus for aldosterone secretion, followed by renin secretion, excess potassium, and sodium deficiency. Additional factors that stimulate aldosterone synthesis include atrial natriuretic peptide, adrenocorticotropic hormone²⁰, and the lipid-soluble factor produced by adipose tissue, especially in the abdominal region^8,9. Aldosterone plays a key role in electrolyte homeostasis and blood pressure regulation by controlling sodium transport via mineralocorticoid receptors; these receptors are widely distributed, thus corroborating evidence of the deleterious effects of abnormal aldosterone levels^3,21.

Studies on the factors involved in aldosterone regulation led to the discovery of the RAAS, and consequently, to the further clarification of the mechanisms of blood pressure regulation¹. The RAAS is associated with obesity, dyslipidemia, insulin resistance, and high blood pressure²².

Once renin is secreted, it acts on the circulating angiotensinogen (a renin substrate), leading to the production of angiotensin I, which in turn is converted into angiotensin II in the lungs by the angiotensin-converting enzyme. Angiotensin II increases the expression of aldosterone synthase (CYP11B2) and steroidogenic acute regulatory protein (StAR), a transport protein that regulates cholesterol transfer within mitochondria, leading to the synthesis of pregnenolone, one of the precursors of aldosterone. This mechanism strongly stimulates aldosterone synthesis. Moreover, angiotensin II is a potent vasoconstrictor and plays a direct role in intravascular volume depletion².

Dietary Factors and Aldosterone Modulation

Excessive food intake and quality of nutrients including fat, carbohydrates, and salt, is associated with increased adipose tissue²³ and levels of RAAS components⁹. Experimental studies demonstrate that excessive aldosterone levels associated with insulin resistance may lead to myocardial rigidity and diastolic dysfunction in response to excessive food intake¹⁶. Rats fed a high-fat diet for 8-11 weeks showed twice the angiotensinogen gene expression levels in retroperitoneal adipose tissue as well as increased plasma levels of angiotensin II, which are correlated with mean arterial pressure²⁴ (Table I).

The serum concentrations of sodium and potassium are among the main factors that stimulate aldosterone synthesis. However, the effects of a high-sodium diet on plasma aldosterone levels are unknown. Although the concentrations of these electrolytes are strictly regulated by diverse homeostatic mechanisms, a high-sodium diet is expected to lead to increased serum sodium and potassium levels, and consequently, to decreased aldosterone synthesis. The opposite is expected to occur with a sodium-restricted diet, which would lead to increased aldosterone synthesis by the adrenal glands and a consequent increase in sodium absorption by the kidneys. A meta-analysis demonstrates an association between sodium restriction and increased serum levels of aldosterone and renin²⁶. However, high salt intake in rats is postulated to increase inflammation and oxidative stress, thus leading to diastolic dysfunction in the presence of elevated concentrations of aldosterone and angiotensin II²⁷. A study performed in sheep evaluated the effects of high- and low-sodium diets for 2 months during gestation²⁸. The results demonstrate associations among kidney function, hormone levels, and the mRNA (messenger ribonucleic acid) expressions of proteins of the RAAS in both fetuses and offspring. Some alterations observed in fetuses, including increased angiotensinogen gene expression, angiotensin-converting enzyme, and angiotensin I and II receptors, were still present after birth, suggesting possible risks for the development of cardiovascular and kidney diseases (Table I). These results provide further evidence of the benefits of reduced sodium intake along with a healthy diet, particularly decreased blood pressure²⁹.

In an experimental study, rats fed a fructose-rich diet exhibited decreased ectopic deposition of intramuscular lipids caused by RAAS blockade³⁰; moreover, rats fed a fructose- and fat-rich diet had reduced fat tissue hypertrophy and macrophage infiltration as well as fewer metabolic alterations (e.g. steatohepatitis, dyslipidemia, high blood pressure, and glucose intolerance/ insulin resistance) when administered spironolactone for 12 weeks³¹. Furthermore, aldosterone increases glucose intolerance and insulin resistance induced by fructose via the activation of mineralocorticoid receptors³² (Table I).

Diet may have different effects on aldosterone, thus suggesting that this hormone is influenced by mechanisms other than the sodium homeostasis feedback mechanism and blood pressure. The consumption of fat- and/or fructose-rich diets is associated with higher aldosterone levels. However, the various mechanisms involved in this process as well as patterns and diet components associated with hormonal status are not fully understood.

Aldosterone and Obesity

Adipose tissue is considered an integral part of the endocrine and immune systems³³. Obesity, characterized by an increase in the amount of adipose tissue, is associated with the increased synthesis of pro-inflammatory and atherogenic substances such as angiotensinogen, leptin, non-esterified fatty acids, reactive oxygen species, resistin³⁴, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and prothrombotic factors such as plasminogen activator inhibitor-1 (PAI-1) as well as reduced synthesis of adiponectin and peroxisome proliferator-activated receptor gamma (PPAR-γ)³⁵. These alterations in adipokine production are directly related to the activation of the RAAS by adipose tissue, which is partially mediated by angiotensin II²².

Aldosterone is hypothesized to promote adipogenesis; the resultant adipose tissue then mutually increases aldosterone synthesis¹⁸. Thus, the control of aldosterone synthesis may differ according to the location of the adipose tissue. Abdominal adipocytes are more closely associated with the hypersecretion of trophic factors that result in aldosterone biosynthesis²¹. Angiotensino-gen and angiotensin II receptor gene expression levels are higher in visceral adipose tissue than in abdominal subcutaneous adipose tissue; this is associated with higher growth and proliferation of adipocytes in visceral adipose tissue³⁶. However, the lower activity of the RAAS in gluteofemoral adipose tissue may explain why the fat from this area is less metabolically active⁹.

A recent study investigated the effects of adiposity on the plasma levels of aldosterone in children and adolescents; the results show significant associations between aldosterone level and body mass index (BMI), waist and hip circumference, and tricipital and subscapular skinfolds for Caucasian but not African-American subjects³⁷. Another study shows associations between plasma aldosterone level and BMI, waist circumference, and waist-to-height ratio in African-American adult subjects³⁸.

The fact that obese subjects have lower plasma aldosterone levels as well as decreased insulin resistance after experiencing weight loss further corroborates the association between aldosterone and adipose tissue content³⁹ (Table I).

Therefore, the studies described above demonstrate a strong association between adipose tissue and aldosterone, in which high concentrations of this hormone are related to adiposity, particularly abdominal fat. Furthermore, the location of the fat appears to play an important role in adrenal steroidogenesis, and fat from the gluteal muscles appears to exhibit an inverse relationship. Despite these findings, the pathophysiological mechanisms involving the RAAS and adipose tissue are not fully understood.

A study involving African-American subjects revealed differences in plasma fasting glucose levels, blood insulin levels, and homeostasis model assessment-estimated insulin resistance (HOMA-IR) with respect to aldosterone levels; subjects with "moderate" concentrations of aldosterone had higher values than those with "low" concentrations⁴⁰.

Kidambi et al.³⁸ also found positive associations of aldosterone with blood insulin levels and HOMA-IR. They proposed that the increased synthesis of aldosterone likely occurs because of hyperinsulinemia or the release of adipokines by visceral adipose tissue. It is important to note that cross-sectional studies preclude the establishment of causal relationships, because the cause and effect factors cannot be identified. Increased angiotensin II synthesis also interferes with insulin signaling in muscles because of oxidative stress and endothelial dysfunction as well as decreased resistin production⁹.

Hyperaldosteronism associated with obesity not only aggravates pancreatic β-cell function but also leads to decreased insulin signaling in skeletal muscle¹⁸. Another proposed mechanism involves a reduction in the gene expression of the insulin receptor by aldosterone. Aldosterone may also affect insulin sensitivity by interfering with potassium metabolism¹⁷. Aldosterone administration in rats resulted in a dose-dependent increase in blood glucose levels through the increased expression of the genes involved in gluconeogenesis¹².

Experimental and epidemiologic studies suggest a relationship between increased aldosterone levels and the presence of insulin resistance. Several pathophysiological mechanisms have been proposed; they include genomic mechanisms, such as interference with the synthesis of hepatic enzymes involved in glucose metabolism, as well as non-genomic mechanisms, such as increased synthesis of inflammatory adipokines, which aggravate insulin resistance.

Aldosterone and Dyslipidemia

Plasma aldosterone and not renin is associated with the levels of total cholesterol, low-density lipoprotein (LDL), and triglycerides³⁸. Excessive aldosterone levels stimulate adipocyte dysfunction, leading to an increased release of free fatty acids, which may cause an increase in very-low-density lipoprotein (VLDL), and thus result in hepatic steatosis and ectopic fat accumulation⁹. The resultant increased levels of VLDL produced by the liver reach the circulation, where lipid changes occur between the subclasses of LDL and high-density lipoprotein (HDL), which become smaller and denser. This results in increased HDL uptake and subsequent renal excretion, thus consequently decreasing serum levels of HDL and the associated protection. LDL particles become more easily oxidized, and hence more atherogenic; there is also an increase in the synthesis of other lipoproteins. This pattern of dyslipidemia is often observed in patients with type 2 diabetes mellitus and/or with metabolic syndrome³³.

Furthermore, Goodfriend et al.⁴¹ demonstrate a strong negative correlation between aldosterone and HDL. However, patients with higher aldosterone levels also had higher BMI and waist-to-hip ratio, suggesting that adipose tissue and not aldosterone caused the observed dyslipidemia. Moreover, the Framingham Heart Study, which included 2,891 subjects, did not show a correlation between low HDL levels and high aldosterone levels⁴²; this indicates that high blood pressure and not aldosterone is associated with the observed effects on lipid homeostasis. Nevertheless, additional studies are required to better understand the direct and indirect effects of aldosterone on the lipid profile.

Aldosterone and High Blood Pressure

As a component of the RAAS, aldosterone is classically known as a factor contributing to the development of high blood pressure, owing to its role in sodium and water retention¹⁰. The activation of the RAAS along with increased aldosterone levels is strongly associated with high blood pressure as well as other components of metabolic syndrome in humans^{11,13,14,38,43} and animal models^12,15,16 (Table I). This can be explained by the fact that aldosterone inhibits nitric oxide-mediated endothelium-dependent relaxation by decreasing its bioavailability because of the increased reactive oxygen species level. Thus, an increased aldosterone level is associated with greater endothelial dysfunction and the subsequent development of high blood pressure¹⁸.

In a cohort study of 1,688 normotensive subjects, aldosterone was associated with increased blood pressure, suggesting that higher levels of this hormone-even if within normal parameters-is a predisposing factor to the development of high blood pressure⁴⁸.

Thus, it appears that the development and progression of high blood pressure are the most evident cardiometabolic alterations related to the adverse effects of excess aldosterone. Mineralocorticoid receptor antagonists have been shown to be effective for the treatment of patients with treatment-resistant hypertension and associated metabolic alterations.

Aldosterone in Subclinical Inflammation and Oxidative Stress

Aldosterone appears to affect the development of cardiovascular diseases via mechanisms besides mineralocorticoid receptors. This process involves higher infiltration of macrophages into the adipose tissue, which contributes to increased oxidative stress caused by NAD(P)H oxidase through the stimulation of the expression of pro-inflammatory genes such as those from adhesion molecules and chemokines. This ultimately increases cardiovascular risk⁴⁹. Oxygen radicals may promote oxidative damage, structural remodeling, inflammation, and atrial fibrillation; these in turn activate angiotensin II and independent cascades, leading to increased aldosterone synthesis, which is associated with tissue damage⁵⁰.

In animal experiments, systemic aldosterone administration causes oxidative stress and myocardial inflammation. Moreover, the inhibition of reactive oxygen species prevents inflammation and adverse cardiac remodeling in rats, suggesting that these mechanisms are involved in the adverse effects of aldosterone on the myocardium⁵¹ (Table I).

A cohort study performed with 3,770 hypertensive human subjects investigated the relationship between the degree of inflammatory activation and urinary aldosterone concentration⁵². The results show that aldosterone is associated with C-reactive protein and serum amyloid A protein, which suggests that aldosterone is involved in the occurrence of subclinical inflammation at least in individuals with essential hypertension. After adjusting for age, sex, race, diabetes mellitus, smoking habit, heart rhythm, left ventricular mass, and BMI, in individuals with heart failure caused by systolic dysfunction (n = 58), aldosterone was not correlated with C-reactive protein (an inflammatory marker) but rather with 8-iso-prostaglandin F2α (an oxidative stress marker), intercellular adhesion molecule 1 (ICAM-1) (an endothelial dysfunction marker), and tissue inhibitor of metalloproteinases-1 (a marker of turnover of tissue matrix). The authors state that aldosterone may have distinct effects on the different aspects of inflammation, during which ICAM-1 is present on the surfaces of endothelial cells and myocytes, and C-reactive protein is produced in the liver and acts as an acute phase reactant and a marker of generalized inflammation. However, it is important to mention that the small sample size of this study is a limiting factor; thus, additional relationships between aldosterone and other biomarkers may be detected with a larger sample size¹³.

It is important to note that oxidative stress increases inflammation, which in turn aggravates endothelial dysfunction, leading to increased oxidative stress. Both factors may affect the interstitial matrix by acting on the synthesis and degradation of myocardial collagen⁵³.

However, further studies, particularly intervention and cohort studies, are required to better understand the endocrinal associations between the various markers of subclinical inflammation and oxidative stress with respect to the clinical and ethnic aspects of various populations.

Aldosterone and Metabolic Syndrome

Evidence supports the hypothesis that aldosterone levels can predict the onset of high blood pressure and metabolic syndrome. In the Framingham Offspring Study, 2,292 subjects were evaluated to determine the relationships between the incidence of metabolic syndrome and 8 markers associated with homeostasis, inflammation, endothelial dysfunction, and neurohormonal activity. Following adjustment for confounders, only the levels of PAI-1 and aldosterone were associated with metabolic syndrome. PAI-1 is known to contribute to tissue fibrosis, and aldosterone increases PAI-1 expression levels⁵⁵. PAI-1 is significant and positively associated with longitudinal changes in systolic arterial pressure, plasma fasting glucose levels, and triglycerides, while aldosterone is associated with systolic arterial pressure¹⁴.

The results of a cross-sectional study evaluating the influence of aldosterone on metabolic syndrome development indicated correlations between aldosterone level and blood pressure, waist circumference, blood insulin levels, HOMA-IR, and dyslipidemia. Individuals with metabolic syndrome are reported to have higher aldosterone and aldosterone/renin levels³⁸. Another similar study showed that aldosterone levels and waist circumference in men were correlated and that aldosterone levels increased with age. Moreover, subjects with metabolic syndrome had aldosterone levels approximately 20% higher than those of metabolically normal individuals⁴³.

In order to corroborate these findings, a clinical triage study was conducted to monitor diet intervention (i.e. with or without sodium restriction) and physical activity for 1 year in 285 overweight young adults without additional risk factors⁵⁶ (Table I). After adjusting for age, sex, time and type of intervention, and sodium and potassium excretion, the results indicated associations of decreased aldosterone levels with decreased C-reactive protein, leptin, insulin, HOMA-IR, and heart rhythm values and increased adiponectin levels. These findings suggest that favorable changes in obesity-related factors are associated with decreased circulating levels of aldosterone, thus reinforcing the role of aldosterone as an emergent and important cardiometabolic risk factor.

The studies summarized above suggest increased aldosterone levels may be a relevant risk factor for the development and progression of metabolic syndrome, which is supported by the parallel relationship between the control of metabolic syndrome components and hormonal decline. Thus, aldosterone can be used to help identify individuals with higher cardiometabolic risk. Furthermore, this hormone may be considered a component of metabolic syndrome in the future.

Aldosterone and Cardiovascular Disease

Exposure to high levels of aldosterone, such as in cases of primary aldosteronism, leads to higher rates of cardiovascular morbidity and mortality. The results of a case-control study that compared patients with primary aldosteronism to those with essential hypertension indicated higher blood pressure levels, family history of early cardiovascular disease, left ventricular hypertrophy, and higher cardiovascular risk in cases of primary aldosteronism⁵⁷. Another study comparing patients with primary aldosteronism to those with essential hypertension shows that primary aldosteronism is associated with a 2-fold greater prevalence of left ventricular hypertrophy, even after adjusting for the duration of hypertension as well as higher prevalence of coronary arterial disease (odds ratio [OR] = 1.9), myocardial infarction (OR = 2.6), heart failure (OR = 2.9), and atrial fibrillation (OR = 5.0)⁵⁸.

The cardiovascular effects of aldosterone stem from its influence on the excretion of electrolytes and fluids, which in turn affects blood volume and pressure⁴⁵. However, independent of its effects on electrolyte and fluid reabsorption, aldosterone also acts specifically on the heart muscle, leading to effects such as hypertrophy, cardiac arrhythmia, sympathetic nervous system activation, parasympathetic nervous system inhibition, endothelial dysfunction, vascular inflammation, and myocardial fibrosis and congestion; these effects on the heart muscle appear to result from vascular fibrosis, inflammation, and endothelial dysfunction^17,59.

The pro-inflammatory and prothrombotic effects of aldosterone on the cardiovascular system promote hypertrophy and remodeling of the left ventricle; they are also associated with increased cardiovascular morbidity/mortality and total mortality in populations with high cardiovascular risk, including those with cardiac insufficiency, myocardial infarction, and a high risk of coronary arterial disease². A study of 129 hypertensive subjects evaluated several markers of cardiovascular risk, including lipids, blood glucose levels, blood insulin levels, HOMA-IR, C-reactive protein levels, microalbuminuria, homocysteine levels, aldosterone levels, renin levels, and endothelin levels. Among these, aldosterone and endothelin levels were the most important determinants of left ventricular hypertrophy⁶⁰.

Despite its effects on high-risk groups, aldosterone also affects subgroups of patients with stable and low risks of coronary arterial disease; this was evident in an observational prospective study demonstrating the relationships among aldosterone, vascular events, and atherosclerotic load in 2,699 outpatients with coronary arterial disease (age >60 years; 82 men)¹⁰. During a median follow-up period of 4.7 years, the vascular outcomes of myocardial infarction, ischemic stroke, or vascular death were noted in 355 (13%) patients. Moreover, aldosterone levels were independently associated with future vascular events (incidence ratio: 1.56, 95% confidence interval [CI]: 1.13-2.15) and vascular death (incidence ratio: 1.95, 95% CI: 1.27-3.00). Bivariate analysis also demonstrated significant associations of aldosterone levels with the presence and degree of atherosclerosis in additional vascular territories (i.e. cerebrovascular disease or peripheral artery disease; p = 0.026). These results collectively suggest a strong etiologic association between the aldosterone pathway and the atherosclerotic process, although this cannot be generalized to other populations. This relationship is very important in clinical practice because it is relevant to the evaluation of high-risk patients, thus enabling easier and more effective monitoring as well as identification of patients who will benefit from therapeutic strategies that are more intensive^10,60.

The expansion of the role of aldosterone as a risk factor for cardiovascular events is primarily based on the efficacy of mineralocorticoid receptor antagonists under these conditions^21,61. Left ventricular hypertrophy, an independent cardiovascular risk factor, was reduced and normalized in 57% of patients who were administered low-dose spironolactone for 3 years⁶². Aldosterone antagonists act by suppressing the deleterious effects of this hormone on the components of metabolic syndrome, thus decreasing the risk of the development of cardiovascular diseases (Figure I).

The inappropriate activation of the RAAS and inability of the body to decrease aldosterone levels in response to a sodium-rich diet, which is typical at nowadays, illustrate the poor adaptation of this regulatory system⁶¹.

Conclusions and Perspectives

Studies performed since the discovery of aldosterone demonstrate that in addition to its classical roles in electrolyte homeostasis and blood pressure regulation, aldosterone plays important roles in metabolic disorders and cardiovascular diseases. Obesity, particularly in the visceral area, has been recognized as an important regulatory mechanism for aldosterone synthesis, which may partially explain the association between adipose tissue and metabolic syndrome. Quantitative and qualitative dietary factors affect aldosterone level; high fructose and fat intake leads to increased aldosterone levels, while the effects of a sodium-rich diet on aldosterone remain controversial. Therefore, additional research is required to clarify the effects of sodium on aldosterone as well as the roles of other diet components.

Indeed, the studies presented herein consider aldosterone to be a hormone related to cardiometabolic risks due to its associations with high blood pressure, insulin resistance, dyslipidemias, oxidative stress/subclinical inflammation, and increased cardiovascular morbidly and mortality.

Acute and chronic elevations of circulating levels of aldosterone, even if within normal parameters, are associated with increased risks of infarction, stroke, and mortality due to cardiovascular events. In this context, the use of mineralocorticoid receptor antagonists to inhibit the complex RAAS represents a promising therapeutic option for the prevention and treatment of these comorbidities.

Conflicts of Interest

References

1. Horton R. Aldosterone and aldosteronism. Steroids 2003;68: 1135-38.         [ Links ]

2. White BA, Porterfiedl SP. Endocrine and reproductive physiology. Monograph series. 4 ed. Elsevier 2012. 297p.         [ Links ]

3. Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension 2005;46:1227-35.         [ Links ]

4. Takeda Y, Miyamori I, Yoneda T Iki K, Hatakeyama H, Blair IA, et al. Production of aldosterone in isolated rat blood vessels. Hypertension 1995;25:170-3.         [ Links ]

5. Gomez-Sanchez CE, Zhou MY, Cozza EN, Morita H, Foecking MF, Gomez-Sanchez EP. Aldosterone biosynthesis in the rat brain. Endocrinology 1997;138:3369-73.         [ Links ]

6. Takeda Y, Yoneda T, Demura M, Miyamori I, Mabuchi H. Sodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy. Endocrinology 2000; 141:1901-4.         [ Links ]

7. Gomez-Sanchez EP, Ahmad N, Romero DG, Gomez-Sanchez CE. Origin of aldosterone in the rat heart. Endocrinology 2004;145:4796-4802.         [ Links ]

8. Krug AW, Ehrhant-Bornstein M. Aldosterone and metabolic syndrome: is increased aldosterone in metabolic syndrome patients an additional risk factor. Hypertension 2008;51:1252-58.         [ Links ]

9. Marcus Y, Shefer G, Stern N. Adipose tissue rennin-angiotensin-aldosterone system (RAAS) and progression of insulin resistance. Mol Cell Endocrinol 2013;378:1-14.         [ Links ]

10. Hillaert MA, Lentjes EG, Kemperman H, van der Graaf Y, Nathoe HM, Beygui F, et al. Aldosterone, atherosclerosis and vascular events in patients with stable coronary artery disease. Int J Cardiol 2013;167:1929-35.         [ Links ]

11. Goodfriend TL, Kelley DE, Goodpaste BH, Winters SJ. Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obesity Research 1999;7(4):355-62.         [ Links ]

12. Yamashita R, Kikuchi T, Mori Y, Aoki K, Kaburagi Y, Yasuda K, et al. Aldosterone stimulates gene expression of hepatic gluconeogenic enzymes through the glucocorticoid receptor in a manner independent of the protein kinase B cascade. Endocr J 2004;51:243-51.         [ Links ]

13. Kotlyar E, Vita JA, Winter MR, Awtry EH, Siwik DA, Keaney JF J, et al. The relationship between aldosterone, oxidative stress and inflammation in chronic, stable human heart failure. J Card Fail 2006;12(2):122-7.         [ Links ]

14. Ingelsson E, Pencina MJ, Tofler GH, Benjamin EJ, Lanier KJ, Jacques PF, et al. Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors. The Framingham Offspring Study. Circulation 2007;116:984-92.         [ Links ]

15. Kawahito H, Yamada H, Irie D, Kato T, Akakabe Y, Kishida S, et al. Periaortic adipose tissue-specific activation of the renin-angiotensin system contributes to atherosclerosis development in uninephrectomized apoE-/-mice. Am J Physiol Heart Circ Physiol 2013; 305(5):667-75.         [ Links ]

16. Manrique CAB, DeMarco VG, Aroor AR, Mugerfeld I, Garro M, Habibi J, et al. Obesity and insulin resistance induce early development of diastolic dysfunction in young female mice fed a western diet. Endocrinology 2013;154(10):3632-42.         [ Links ]

17. Vogt B, Burnier M. Aldosterone and cardiovascular risk. Curr Hypertens Rep 2009;11:450-455.         [ Links ]

18. Whaley-Connell A, Johnson MS, Sowers JR. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog Cardiovasc Dis 2010;52(5):401-409.         [ Links ]

19. White P. Inherited forms of mineralocorticoid hypertension. Hypertension 1996; 28:927-36.         [ Links ]

20. Müller J. Aldosterone: The minority hormone of the adrenal cortex. Steroids 1995;60:2-9.         [ Links ]

21. Funder JW, Reincke M. Aldosterone: a cardiovascular risk factor? Biochim Biophys Acta 2010;1802(12):1188-92.         [ Links ]

22. Jim F, Mogi M, Horiuchi M. Role of renin-angiotensin-aldosterone system in adipose tissue dysfunction. Mol Cell Endocrinol 2013;378:23-28.         [ Links ]

23. Navia B, Aparicio A, Perea JM, Perez-Farinös N, Villar-Villalba C, Labrado E, et al. Sodium intake may promote weight gain; results of the FANPE study in a representative sample of the adult Spanish population. Nutr Hosp 2014;29(6):1283-89.         [ Links ]

24. Boustany CM, Bharadwaj K, Daugherty A, Brown DR, Randall DC, Cassis LA. Activation of the systemic and adipose rennin-angiotensin system in rats with diet-induced obesity and hypertension. Am J Physiol Regul Integr Comp Physiol 2004;287:943-49.         [ Links ]

25. Conway V, Couture P, Gauthier S, Pouliot Y, Lamarche B. Effect of buttermilk consumption on blood pressure in moderately hypercholesterolemic men and women. Nutrition 2014;30(1):116-19.         [ Links ]

26. Graudal NA, Hubeck-Graudal T, Jürgens G. Effects of low-sodium diet vs. high-sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride. Am J Hypertens 2012;25(1):1-15.         [ Links ]

27. Whaley-Connell AT, Habibi J, Aroor A, Ma L, Hayden MR, Ferrario CM, et al. Salt loading exacerbates diastolic dysfunction and cardiac remodeling in young female Ren2 rats. Metabolism 2013;62(12):1761-71.         [ Links ]

28. Mao CA, Liu R, Bo L. High-salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system. J Endocrinol 2013;128(1): 61-73.         [ Links ]

29. Appel LJ and American Society of Hypertension Writing Group. ASH position paper: dietary approaches to lower blood pressure. J Clin Hypertens 2009;11(7):358-68.         [ Links ]

30. Furuhashi M, Ura N, Takizawa H, Yoshida D, Moniwa N, Murakami H, et al. Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity. J Hypertens 2004;22(10):1977-82.         [ Links ]

31. Wada TA, Miyashita Y, Sasaki M, Aruga Y, Nakamura Y, Ishii Y, et al. Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet. Am J Physiol Endocrinol Metab 2013;305(11):1415-25.         [ Links ]

32. Sherajee SJ, Rafiq K, Nakano D, Mori H, Kobara H, Hitomi H, et al. Aldosterone aggravates glucose intolerance induced by high fructose. Eur J Pharmacol 2013; 720(15):63-68.         [ Links ]

33. Bays HE, Toth PP, Kris-Etherton, Abate N, Aronne LJ, Brown WV, et al. Obesity, adiposity, and dyslipidemia: A consensus statement from the National Lipid Association. J Clin Lipidol 2013;7:304-83.         [ Links ]

34. Canale MP, di Villahermosa SM, Martino G, Rovella V, Noce A, De Lorenzo A, et al. Obesity-related metabolic syndrome: mechanisms of sympathetic overactivity. Int J Endocrinol 2013;2013:865-965.         [ Links ]

35. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005;96(9):939-49.         [ Links ]

36. Giacchetti G, Faloia E, Mariniello B, Sardu C, Gatti C, Camilloni MA, et al. Overexpression of the rennin-angiotensin system in human visceral adipose tissue in normal and overweight subjects. Am J Hypertens 2002;15:381-88.         [ Links ]

37. Yu Z, Eckert GJ, Liu H, Pratt JH, Tu W. Adiposity has unique influence on the renin-aldosterone axis and blood pressure in black children. J Pediatr 2013;163(5):1317-22.         [ Links ]

38. Kidambi S, Kotchen JM, Grim CE, Raff H, Mao J, Singh RJ, et al. Association of adrenal steroids with hypertension and the metabolic syndrome in blacks. Hypertension 2007;49:704-11.         [ Links ]

39. Dall'Asta C, Vedani P, Manunta P, Pizzocri P, Marchi M, Paganelli M, et al. Effect of weight loss through laparoscopic gastric banding on blood pressure, plasma renin activity and aldosterone levels in morbid obesity. Nutr Metab Cardiovasc Dis 2009;19:110-14.         [ Links ]

40. Huan Y, DeLoach S, Keith SW, Goodfriend TL, Falkner B. Aldosterone and aldosterone: renin ratio associations with insulin resistance and blood pressure in African Americans. J Am Soc Hypertens 2012;6(1): 56-65.         [ Links ]

41. Goodfriend TL, Egan B, Stepniakowski K, Ball DL. Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans. Hypertension 1995;25:30-36.         [ Links ]

42. Kathiresan S, Larson MG, Benjamin EJ, Corey D, Murabito JM, Fox CS, et al. Clinical and genetic correlates of serum aldosterone in the community: the Framingham Heart Study. Am J Hypertens 2005;18:657-65.         [ Links ]

43. Bochud M, Nussberger J, Bovet P, Maillard MR, Elston RC, Paccaud F, et al. Plasma aldosterone is independently associated with the metabolic syndrome. Hypertension 2006;48:239-45.         [ Links ]

44. Strauch B, Zelinka T, Hampf M, Bernhardt R, Widimsky J Jr, et al. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens 2003;17(5):349-52.         [ Links ]

45. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1125 hypertensive patients. J Am Coll Cardiol 2006;48:2293-2300.         [ Links ]

46. Sowers JR, Whaley-Connell A, Epstein M. The emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistance hypertension. Ann Intern Med 2009;150:776-83.         [ Links ]

47. Ikeda K, Isaka T, Fujioka K, Manome Y, Tojo K. Suppression of aldosterone synthesis and secretion by ca(2+) channel antagonists. Int J Endocrinol 2012; 2012: 519467.         [ Links ]

48. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004;351:33-41.         [ Links ]

49. Yoshimotoa T, Hirata Y. Aldosterone as a cardiovascular risk hormone. J Endocrinol 2007;54(3):359-70.         [ Links ]

50. Mayyas F, Alzoubi KH, Van Wagoner DR. Impact of aldosterone antagonists on the substrate for atrial fibrillation: Aldosterone promotes oxidative stress and atrial structural/electrical remodeling. Int J Cardiol 2013;166(6):5135-42.         [ Links ]

51. Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT, et al. Aldosterone induced inflammation in the heart: role of oxidative stress. Am J Pathol 2002;161:1773-81.         [ Links ]

52. Tzamou V, Vyssoulis G, Karpanou E, Kyvelou SM, Gialernios T, Stefanadis C, et al. Aldosterone levels and inflammatory stimulation in essential hypertensive patients. J Hum Hypertens 2013;27:535-38.         [ Links ]

53. Siwik DA, Colucci WS. Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardium. Heart Fail Rev 2004;9 (1):43-51.         [ Links ]

54. Egan BM, Papademetriou V, Wofford M, Calhoun D, Fernandes J, Riehle JE, et al. Metabolic syndrome and insulin resistance in the TROPHY sub-study: Contrasting views in patients with high-normal blood pressure. Am J Hypertens 2005;18(1):3-12.         [ Links ]

55. Enomoto S, Yoshiyama M, Omura, Matsumoto R, Kusuyama T, Kim S T, et al. Effects of eplerenone on transcriptional factors and mRNA expression related RO cardiac remodeling after myocardic infarction. Heart 2005;91(12):1595-1600.         [ Links ]

56. Cooper JN, Fried L, Tepper P, Barinas-Mitchell E, Conroy MB, Evans RW, et al. Changes in serum aldosterone are associated with changes in obesity-related factors in normo-tensive overweight and obese young adults. Hypertens Res 2013;36(10):895-901.         [ Links ]

57. Abad-Cardiel M, Alvarez-Álvarez B, Luque-Fernandez L, Fernández C, Fernández-Cruz A, Martell-Claros N, et al. Hypertension caused by primary hyperaldosteronism: increased heart damage and cardiovascular risk. Rev Esp Cardiol 2013;66(1):47-52.         [ Links ]

58. Savard S, Amar L, Plouin PF, Steicheb O. Cardiovascular complications associated with primary aldosteronism: A controlled cross-sectional study. Hypertension 2013; 62(2):331-36.         [ Links ]

59. Dartsch T, Fischer R, Gapelyuk A, Weiergraeber M, Ladage D, Schneider T, et al. Aldosterone induces electrical remodeling independent of hypertension. Int J Cardiol 2013;5(164):170-78.         [ Links ]

60. Peer M, Boaz M, Zipora M, Shargorodsky M. Determinants of left ventricular hypertrophy in hypertensive patients: identification of high-risk patients by metabolic, vascular, and inflammatory risk factors. Int J Angiol 2013;22(4):223-28.         [ Links ]

61. Tomaschitz A, Pilz S, Ritz E, Boehm BO, März W. Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk Cardiovascular Health Study (LURIC). Eur Heart J 2010;31(10):1237-47.         [ Links ]

62. Ori Y, Chagnac A, Korzets A, Zingerman B, Herman-Edelstein M, Bergman M, et al. Regression of left ventricular hypertrophy in patients with primary aldosteronism/low-renin hypertension on low-dose spironolactone. Nephrol Dial Transplant 2013;28(7):1787-93.         [ Links ]

Correspondence: ]]> Patrícia Feliciano Pereira.
Federal University of Viçosa.
Nutrition and Health Department.
Avenue PH Rolfs, s/n.
CEP 36.570-900 - Viçosa (MG), Brazil.
E-mail: patricia.pereira@ufv.com.br

Recibido: 29-VI-2014.
Aceptado: 13-VIII-2014.