Carlos E. Fardella

Primary Aldosteronism and Hypertensive Disease

Abstract—Recent studies in hypertensive populations that have used the serum aldosterone (SA) to plasma renin activity (PRA) ratio as a screening test have demonstrated a high prevalence of primary aldosteronism (PA). This frequency is higher than that previously described when hypokalemia was used as a screening tool. However, other factors, such as the characteristics of hypertensive disease, could also influence the prevalence of PA. We studied 609 essential hypertensive patients, classified according to the Joint National Committee VI (JNC VI), in 3 different stages depending on the severity of their hypertensive disease. We measured SA and PRA and calculated the SA-PRA ratio for all patients. An SA-PRA ratio >25 was detected in 63 of 609 patients, and the fludrocortisone test confirmed the PA diagnoses in 37 of 609 (6.1%) cases. PA prevalence according to hypertension stage was as follows: stage 1, 6 of 301 cases (1.99%); stage 2, 15 of 187 cases (8.02%); and stage 3, 16 of 121 cases (13.2%). PA patients were slightly younger than the other hypertensive patients (48.4±10.5 vs 53.6±10.2 years; P <0.05). Serum potassium levels were normal in 36 of 37 PA patients; only 1 patient had minor hypokalemia. Computed tomography scans showed bilateral adrenal enlargement in 7 and an adrenal nodule in 2 cases. In summary, we found a high frequency of PA in essential hypertensives classified in stages 2 and 3 according to the JNC VI. The low frequency of computed tomography scan abnormalities and hypokalemia suggests that the diagnosis for most PA patients corresponds to attenuated forms of the disease.

High sodium intake is associated with increased glucocorticoid production, insulin resistance and metabolic syndrome

High sodium (HS) diet is associated with hypertension (HT) and insulin resistance (IR). We evaluated whether HS diet was associated with a dysregulation of cortisol production and metabolic syndrome (MetS).

A possible association between primary aldosteronism and a lower β-cell function

Objective Primary aldosteronism (PA) is the most common secondary cause of hypertension and recently has been implicated as a cause of impaired glucose tolerance. We investigated the glucose insulin sensitivity and insulin secretion in patients with idiopathic primary aldosteronism. Design Thirty PA patients and 60 essential hypertensive (EH) patients as controls were included, matched (1: 2) by their body mass index (BMI) (29.9 ± 4.3 versus 29.8 ± 5.8 m/kg2), age (53.7 ± 9.4 versus 59.9 ± 8.6 years old) and gender (male/female: 8/22 versus 17/43). In all patients, we measured insulin, total cholesterol, triglycerides, C-peptide and fasting glucose levels. Homeostasis model assessment for insulin resistance (HOMA-IR) and HOMA of pancreatic β-cell function (HOMA-βF) indexes were calculated. We also evaluated the response to spironolactone in 19 PA patients. Results PA patients had higher levels of glucose (5.2 ± 0.7 versus 4.9 ± 0.7 mmol/l; P = 0.017). Insulin levels (10.7 ± 6.5 versus 11.5 ± 5.8 uUI/ml, P = 0.525) and HOMA-IR (2.51 ± 1.59 versus 2.45 ± 1.29 uUI/ml × mmol/l, P = 0.854) were similar in both groups. HOMA-βF index (138.9 ± 89.8 versus 179.8 ± 100.2%, P = 0.049) and C-peptide (0.83 ± 0.63 versus 1.56 ± 0.84 ng/dl, P = 0.0001) were lower in PA patients. Potassium was normal in both groups. Negative correlations between serum aldosterone/plasma renin activity (SA/PRA) ratio and HOMA-βF, and between C-peptide and SA levels were found in all patients. After the spironolactone treatment, we found an increase of C-peptide and insulin levels without changes in HOMA-IR or HOMA-βF. Conclusion Our results showed differences in glucose metabolism between PA patients and those with hypertension suggesting that these findings could probably be determined by a lower β-cell function influenced by aldosterone. These findings highlight the importance of aldosterone in glucose metabolism.

Increased levels of oxidative stress, subclinical inflammation, and myocardial fibrosis markers in primary aldosteronism patients.

Background Patients with primary aldosteronism experience greater left ventricular hypertrophy and a higher frequency of cardiovascular events than do essential hypertensive patients with comparable blood pressure levels. Aldosterone has been correlated with increased oxidative stress, endothelial inflammation, and fibrosis, particularly in patients with heart disease. Aim To evaluate oxidative stress, subclinical endothelial inflammation, and myocardial fibrosis markers in patients with primary aldosteronism and essential hypertension. Design and individuals We studied 30 primary aldosteronism patients and 70 control essential hypertensive patients, matched by age, sex and median blood pressure. For all patients, we measured the serum levels of aldosterone, plasma renin activity, malondialdehyde (MDA), xanthine oxidase, metalloproteinase-9, ultrasensitive C-reactive protein and amino terminal propeptides of type I (PINP), and type III procollagen. We also evaluated the effect of PA treatment in 19 PA individuals. Results PA patients showed elevated levels of MDA (1.70 ± 0.53 versus 0.94 ± 0.65 μmol/l, P <0.001) and PINP (81.7 ± 50.6 versus 49.7 ± 27 mg/l, P = 0.002) compared with essential hypertensive controls. We found a positive correlation between MDA, PINP, and the serum aldosterone/plasma renin activity ratio in primary aldosteronism patients. Clinically, treating primary aldosteronism patients decreased MDA and PINP levels. Conclusion We detected higher levels of MDA and PINP in primary aldosteronism patients, suggesting increased oxidative stress and myocardial fibrosis in these individuals. Treating primary aldosteronism patients reduced MDA and PINP levels, which may reflect the direct effect of aldosterone greater than endothelial oxidative stress and myocardial fibrosis, possibly mediated by a mineralocorticoid receptor.

Epigenetics and arterial hypertension: the challenge of emerging evidence.

Epigenetic phenomena include DNA methylation, post-translational histone modifications, and noncoding RNAs, as major marks. Although similar to genetic features of DNA for their heritability, epigenetic mechanisms differ for their potential reversibility by environmental and nutritional factors, which make them potentially crucial for their role in complex and multifactorial diseases. The function of these mechanisms is indeed gaining interest in relation to arterial hypertension (AH) with emerging evidence from cell culture and animal models as well as human studies showing that epigenetic modifications have major functions within pathways related to AH. Among epigenetic marks, the role of DNA methylation is mostly highlighted given the primary role of this epigenetic feature in mammalian cells. A lower global methylation was observed in DNA of peripheral blood mononuclear cells of hypertensive patients. Moreover, DNA hydroxymethylation appears modifiable by salt intake in a Dahl salt-sensitive rat model. The specific function of DNA methylation in regulating the expression of AH-related genes at promoter site was described for hydroxysteroid (11-beta) dehydrogenase 2 (HSD11B2), somatic angiotensin converting enzyme (sACE), Na+/K+/2Cl- cotransporter 1 (NKCC1), angiotensinogen (AGT), α-adducin (ADD1), and for other crucial genes in endocrine hypertension. Post-translational histone methylation at different histone 3 lysine residues was also observed to control the expression of genes related to AH as lysine-specific demethylase-1(LSD1), HSD11B2, and epithelial sodium channel subunit α (SCNN1A). Noncoding RNAs including several microRNAs influence genes involved in steroidogenesis and the renin-angiotensin-aldosterone pathway. In the present review, the current knowledge on the relationship between the main epigenetic marks and AH will be presented, considering the challenge of epigenetic patterns being modifiable by environmental factors that may lead toward novel implications in AH preventive and therapeutic strategies.

Biochemical and genetic characterization of 11 beta-hydroxysteroid dehydrogenase type 2 in low-renin essential hypertensives.

Background The 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) catalyzes the conversion of cortisol (F) to cortisone (E), avoiding the interaction of cortisol with the mineralocorticoid receptor. If it fails, cortisol will stimulate sodium and water reabsorption, increasing the intravascular volume that suppresses renin and secondarily increase the blood pressure. Objective To look for the possible contribution of a decreased ability of 11βHSD2 to convert cortisol to its inactive metabolite cortisone in the pathogenesis of low renin hypertension (LREH). Patients and methods We studied 64 LREH patients (plasma renin activity, PRA < 1 ng/ml per h), eighty normo-renin essential hypertensives (NREH) (PRA: 1–2.5 ng/ml per h) and 74 normotensives. Serum aldosterone (SA), F, E and serum F/E ratio was determined in all patients. A serum F/E ratio was considered high when it was higher than X + 2SD from the normotensive value. Cytosine-adenine (CA)-repeat microsatellite region in intron 1 of HSD11B2 gene was genotyped in all patients and normotensives volunteers. In 13 LREH with high F/E ratio we performed HSD11B2 gene sequencing. Results LREH had serum F/E ratio higher than NREH and normotensive controls (3.6 (2.9–4.3) versus 2.9 (2.2–4.3) versus 3.0 (2.4–3.7) (P = 0.004), respectively). We observed an inverse relation between F/E ratio and SA and PRA. In NREH and normotensives we did not find correlation between these variables. In the LREH subset the longer 155 bp CA-allele showed the highest serum F/E ratio. No mutations in coding region or short introns were found in LREH patients. Conclusion In this study we show that low-renin essential hypertensives had increased serum cortisol/cortisone ratios as compared with normotensive subjects. This suggest that some essential hypertensives, with suppressed renin activity, may have an impairment in the cortisol inactivation catalyzed by the enzyme 11βHSD2, whose low activity in LREH patients could be associated with the length of CA-repeat microsatellite in intron 1 of the HSD11B2 gene.

Aldosterone as a modulator of immunity: implications in the organ damage

High plasmatic levels of aldosterone cause hypertension and contribute to progressive organ damage to the heart, vasculature, and kidneys. Recent studies have demonstrated a role for the immune system in these pathological processes. Aldosterone promotes an inflammatory state characterized by vascular infiltration of immune cells, reactive oxidative stress, and proinflammatory cytokine production. Further, cells of the adaptive immune system, such as T cells, seem to participate in the genesis of mineralocorticoid hormone-induced hypertension. In addition, the observation that aldosterone can promote CD4⁺ T-cell activation and Th17 polarization suggests that this hormone could contribute to the onset of autoimmunity. Here we discuss recent evidence supporting a significant involvement of the immune system, especially adaptive immunity, in the genesis of hypertension and organ damage induced by primary aldosteronism. In addition, possible new therapeutic approaches consisting of immunomodulator drugs to control exacerbated immune responses triggered by elevated aldosterone concentrations will be described.

Serum 18-Hydroxycortisol in Primary Aldosteronism, Hypertension, and Normotensives

This study reports the determination of plasma 18-hydroxycortisol (18-OHF) using a new and easy enzyme-linked immunosorbent assay (ELISA) method in primary aldosteronism and compares the values found in essential hypertensives and normotensive controls. In primary aldosteronism, we evaluated usefulness of plasma 18-OHF determination and the dexamethasone suppression test in the diagnosis of glucocorticoid-remediable aldosteronism using the genetic test as the gold standard. We studied 31 primary aldosteronism patients, 101 essential hypertensives, and 102 healthy normotensive controls. The plasma 18-OHF was measured using a biotin-avidin enzyme-linked assay by a new and purified polyclonal antibody. The 18-OHF value in primary aldosteronism was 6.3±8.05 nmol/L; this value is significantly higher than the value found in essential hypertensives and normotensive controls (2.81±1.42 and 2.70±1.41 nmol/L, respectively;P <0.0005). In primary aldosteronism, 4 of 31 patients had 18-OHF levels that were 10 times higher than the normal upper limit (2.983 nmol/L). The dexamethasone suppression test in primary aldosteronism patients was positive (serum aldosterone <4 ng/dL) in 13 of 31 cases. A chimeric CYP11B1/CYP11B2 gene was demonstrated in 4 primary aldosteronism patients, corresponding to the same cases that had higher level of 18-OHF. In conclusion, plasma 18-OHF determination by this ELISA method is reliable for detecting glucocorticoid-remediable aldosteronism, and it does so better than the dexamethasone suppression test.

Overexpression of 11β-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue and portal hypercortisolism in non-alcoholic fatty liver disease.

The enzyme 11β‐hydroxysteroid‐dehydrogenase type 1 (11β‐HSD1) catalyses the reactivation of intracellular cortisol. We explored the potential role of 11β‐HSD1 overexpression in visceral adipose tissue (VAT) in non‐alcoholic fatty liver disease (NAFLD) assessing sequential changes of enzyme expression, in hepatic and adipose tissue, and the occurrence of portal hypercortisolism in obese mice. 11β‐HSD1 expression was also assessed in tissues from obese patients undergoing bariatric surgery.

Birth weight is inversely associated with blood pressure and serum aldosterone and cortisol levels in children

Context  Low birth weight has been independently associated with adult hypertension, and renin‐angiotensin system (RAS) plays a role in this connection.