Decreased Aldosterone Levels Research Articles

Effects of Left Atrial Appendage Closure on Neuroendocrine Function in Patients with Nonvalvular Atrial Fibrillation.

BackgroundThe left atrial appendage (LAA) is an organ with neuroendocrine function. It remains unclear whether left atrial appendage closure (LAAC) has physiological effects on neuroendocrine function in patients with nonvalvular atrial fibrillation (NVAF). In the present study, we aimed to investigate the effects of LAAC on neuroendocrine function in patients with NVAF.Material/MethodsWe enrolled 20 patients with NVAF treated by LAAC in Jiangsu Taizhou People’s Hospital from October 2019 to October 2020. Blood samples were collected 1 day before LAAC and 12 months after LAAC. Plasma concentrations of adrenaline, aldosterone, pro-atrial natriuretic peptide (NT-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured.ResultsLAAC was successfully performed in all patients, without serious complications. Compared with the preoperative levels, there was no significant difference in the levels of NT-proANP, NT-proBNP, and epinephrine at 12 months after LAAC (P>0.05). However, there was a significant decrease in aldosterone level at 12 months post-procedure (209.04±132.98 pg/ml) compared with pre-procedure baseline (279.08±166.88 pg/ml, P=0.04). There was no correlation between the compression rate of the occlusion and the reduction of aldosterone (Kendall’s Tau-b=0.159, P=0.351).ConclusionsLAAC can be safely and effectively performed in NVAF patients, and showed no significant effect on the adrenergic system and natriuretic peptides, but had an influence on the RAAS.

Aldosterone secretion during the day: Salivary aldosterone awakening response and daytime levels

BackgroundThe mineralocorticoid hormone aldosterone is a key regulator of the sodium–potassium balance and blood pressure. In excess, aldosterone relates to hypertension and cardiovascular disease (CVD). Here, we systematically investigated aldosterone secretion during the day in terms of salivary aldosterone awakening response (AldAR) and salivary aldosterone daytime levels (AldDay) under controlled conditions in participants’ natural environment including assessment of potential confounding variables. MethodsIn 40 healthy young men, saliva samples for AldAR were collected immediately after awakening and 15, 30, 45, and 60 min thereafter. AldDay levels were measured in 1 h intervals from 9:00–22:00 h. Analyses were complemented by salivary cortisol assessment. Fluid and food intake was standardized and as potential confounders, we assessed awakening time and sleep duration, age, BMI and MAP, as well as chronic stress. ResultsAwakening was followed by significant increases in salivary aldosterone (p = .004, f= 0.31), returning to baseline levels > 60 min later. Longer sleep duration was associated with lower AldAR (p < .001, f= 0.36). Over the course of the day we observed a continuous decrease of AldDay (p < .001, f= 0.45). Longer sleep duration (p = .097, f= .21), later time of awakening (p < .001, f= .29), and higher chronic stress (p = .041, f= .23) were associated with AldDay characteristics. Circadian aldosterone secretion was positively associated with most cortisol measures. ConclusionsWe observed an awakening response in salivary aldosterone and could confirm a decrease in aldosterone levels during the day, comparable to cortisol. Significant confounders were sleep-related variables and chronic stress. Clinical implications of circadian aldosterone secretion with respect to CVD risk remain to be elucidated.

Effect of eplerenone on aldosterone and von Willebrand factor levelsin patients with myocardial infarction and chronic kidney disease

Aim: to study the levels of aldosterone and von Willebrand factor (VWF) in patients with Q-wave acute myocardial infarction (Q-AMI) and underling chronic kidney disease (CKD) using aldosterone antagonists. Materials and methods. The study group consisted of 106 patients with renal dysfunction who were hospitalized for acute Q-AMI. Serum levels of neurohumoral parameters (aldosterone and VWF) were determined in all the patients by enzyme-linked immunosorbent assay kits. Results. Reduction in the aldosterone levels was found in patients with Q-AMI and stage 2 CKD from 245.08 ± 17.38 pmol/l to 195.15 ± 13.82 pmol/l (P &lt; 0.05;) who received spironolactone and from 275.59 ± 23.43 to 169.37 ± 24.46 pmol/l (P &lt; 0.001) with eplerenone usage. Patients with stage 1 CKD showed a decreasing trend in aldosterone levels when using spironolactone (from 238.04 ± 20.37 pmol/l to 200.78 ± 9.15 pmol/l), and significantly decreased aldosterone levels when receiving eplerenone (from 229.77 ± 13.76 pmol/l to 156.76 ± 5.76 pmol/l; P &lt; 0.05). The serum concentration of VWF in stage 2 CKD patients was changed insignificantly on spironolactone therapy (from 0.99 ± 0.13 mg/l to 1.13 ± 0.06 mg/l) and it was significantly decreased in the eplerenone group – from 1.29 ± 0.19 mg/l to 0.71 ± 0.14 mg/l (P &lt; 0.05). In stage 1 CKD patients, the concentration of VWF was not decreased significantly with the use of spironolactone (from 1.22 ± 0.13 mg/l to 1.03 ± 0.06 mg/l), but it was decreased significantly when receiving eplerenone (from 1.14 ± 0.09 mg/l to 0.79 ± 0.08 mg/l; P &lt; 0.05). The data obtained indicate the significantly higher probability of declining both aldosterone (t = 2.91; P &lt; 0.01) and VWF (t = 2.59; P &lt; 0.01) with the use of eplerenone in the complex treatment as compared to the spironolactone administration. Conclusions. The effect of eplerenone to decrease the concentration of aldosterone and VWF is significantly greater than that of spironolactone, especially in AMI patients with stage 2 CKD.

Effects of spironolactone and eplerenone on left ventricular diastolic function and neurohumoral factors in patients with heart failure

Aim. To study the effects of spironolactone and eplerenone on left ventricular diastolic function and neurohumoral factors in patients with heart failure (HF).Material and methods. We examined 131 patients with coronary artery disease and NYHA class I-III HF. Patients were randomized into groups depending on HF class: class I (n=31), class II (n=51) and class III (n=49).Results. The study revealed that the clinical course of HF and LV diastolic dysfunction are associated with an increased level of neurohormones and are characterized by significantly high levels of aldosterone and norepinephrine in patients with a restrictiveLV diastolic dysfunction. A correlation was found between the level of neurohormones (aldosterone and norepinephrine) and heart remodeling parameters: an inverse correlation with an ejection fraction (r=-0,68, r=-0,61, respectively) and a direct correlation with LV end-diastolic volume (r=0,58, r=0,66, respectively). Long-term treatment with spironolactone and eplerenone had a positive effect, reducing the level of mentioned neurohormones. In patients with class II HF, both drugs had a positive effect on the level of aldosterone and norepinephrine, reducing them by 26,6% and 20,2% in the spironolactone group and by 28,4% and 24,6% in the eplerenone group, respectively. In patients with class III HF, the decrease in aldosterone level was more pronounced in those taking eplerenone than spironolactone: 32,1% vs 20,2%, respectively.Conclusion. In patients with HF, combination therapy with the inclusion of spironolactone significantly reduced the level of neurohormones mainly in patients with class II HF and, to a lesser extent, in those with class III HF. This suggests that combination therapy with spironolactone is less effective than with eplerenone in relation to neurohormones’ levels.

Dynamic changes of renin-angiotensin-aldosterone system parameters after surgery of primary hyperparathyroidism

To study an activity of the Renin-Angiotensin-Aldosterone System (RAAS) components in patients with primary hyperparathyroidism (PHPT) before and after parathyroidectomy (PTE). A comparative study of patients with PHPT and control group. The first stage of the study included 56 patients with PHPT (group 1) before and on the third day after PTE. The second stage was carried out in 27 patients with remission of PHPT (group 2). All patients and healthy volunteers were tested for the main parameters of phosphorus-calcium metabolism and the RAAS parameters (plasma renin activity PRA, serum aldosterone, angiotensin II AT II). Patients with active PHPT demonstrated changes in RAAS activity (lower PRA, higher AT II level) comparing to control group, that have statistical significance in group 1 (p0.001 for both parameters). There were no significant differences in aldosterone levels (p1=0.090;p2=0.140). On the third day after PTE (group 1), a decrease in aldosterone level (p=0.009) and a tendency to decrease in PRA (p=0.030) were detected. However, an increase in PRA (p=0.018), a decrease in AT II concentration (p=0.032) comparing to the initial values and their normalization were observed 12 months after surgery when permanent normal serum calcium and PTH levels had been achieved. There were controversial correlations between the parameters of phosphorus-calcium metabolism and RAAS. The influence of angiotensin-converting-enzyme inhibitors and AT II receptor blockers on phosphorus-calcium metabolism in patients with PHPT was not observed. In patients with PHPT, there were no сlear correlations of phosphorus-calcium metabolism parameters with RAAS, however an increase of AT II concentration was noted, that can take part in a development of hypertension for this endocrinopathy. PTE can have a positive effect on AT II level.

Lysine-Specific Demethylase-1 Deficiency Increases Agonist Signaling Via the Mineralocorticoid Receptor.

LSD1 (lysine-specific demethylase-1) is an epigenetic regulator of gene transcription. LSD1 risk allele in humans and LSD1 deficiency (LSD1+/-) in mice confer increasing salt-sensitivity of blood pressure with age, which evolves into salt-sensitive hypertension in older individuals. However, the mechanism underlying the relationship between LSD1 and salt-sensitivity of blood pressure remains elusive. Here, we show that LSD1 genotype (in humans) and LSD1 deficiency (in mice) lead to similar associations with increased blood pressure and urine potassium levels but with decreased aldosterone levels during a liberal salt diet. Thus, we hypothesized that LSD1 deficiency leads to an MR (mineralocorticoid receptor)-dependent hypertensive state. Yet, further studies in LSD1+/- mice treated with the MR antagonist eplerenone demonstrate that hypertension, kaliuria, and albuminuria are substantially improved, suggesting that the ligand-independent activation of the MR is the underlying cause of this LSD1 deficiency-mediated phenotype. Indeed, while MR and epithelial sodium channel expression levels were increased in LSD1+/- mouse kidney tissues, aldosterone secretion from LSD1+/- glomerulosa cells was significantly lower. Collectively, these data establish that LSD1 deficiency leads to an inappropriate activation and increased levels of the MR during a liberal salt regimen and suggest that inhibiting the MR pathway is a useful strategy for treatment of hypertension in human LSD1 risk allele carriers.

SAT-059 Treatment Of Primary Aldosteronism With The mTORC1 Inhibitor Everolimus

Background: Primary aldosteronism, characterized by inappropriately high and relatively autonomous aldosterone production, is one of the most frequent causes of secondary hypertension. In most cases, primary aldosteronism results from unilateral or bilateral adrenal hyperplasia and aldosterone-producing adenoma. Depending on the subtype, patient characteristics and preference, treatment comprises unilateral adrenalectomy or mineralocorticoid receptor antagonists. However, these treatments are not always well tolerated or suitable. Histological studies have shown up-regulation of mTOR activity in the adrenal cortex of primary aldosteronism patients and mTORC1 inhibition decreases aldosterone production in adrenocortical cells. Consistently, we found that treatment of mice with the mTORC1 inhibitor rapamycin decreased plasma aldosterone levels without affecting other adrenal steroid hormones. Therefore, we aimed to evaluate the mTORC1-inhibitor everolimus as an aldosterone-lowering drug in patients with primary aldosteronism. Methods: In this open-label, proof-of-concept study, we measured plasma aldosterone levels after a standardized, recumbent saline infusion test in 12 primary aldosteronism patients at baseline, following a two-week everolimus treatment (0.75mg twice daily) and after a two-week washout period. To investigate whether everolimus affects other steroid hormone levels, we measured steroid hormone metabolites in a 24-hour urine collected before each saline infusion test. Results: Median post-infusion plasma aldosterone levels after treatment did not differ significantly from baseline (386 pmol/l, IQR 248-495 vs. 312 pmol/l, IQR 245-426; p = 0.677). However, a marked decrease in aldosterone levels after treatment was observed in four subjects. Their aldosterone levels returned to baseline values after the washout period. This pattern was mirrored by changes in urinary aldosterone/creatinine and tetrahydroaldosterone/creatinine ratios, suggesting that the observed effect was treatment-related. No consistent changes were detected for other steroid metabolites. Conclusion: This is a first in human study on the treatment of primary aldosteronism with the mTORC1 inhibitor everolimus. Overall, we observed a numerical reduction in aldosterone levels after a 2-week treatment which did not reach statistical significance. However, 4 patients appeared to respond to treatment. Further studies with a larger patient cohort are required to further elucidate the effects of mTORC1 inhibitors in primary aldosteronism and to characterize the differences between potential responders and non-responders.

Analysis of clinical manifestations and gene mutations of 13 child patients with rare causes of primary adrenal insufficiency

Objective To analyze the clinical manifestations and gene mutations of rare causes of primary adrenal insufficiency (PAI) in childhood. Methods The clinical features, laboratory tests and gene mutation of 13 patients with PAI in our hospital from September 2010 to August 2017 were analyzed retrospectively. Patients with congenital adrenal hyperplasia, X-linked adrenoleukodystrophy with neurological onset or a clear family history, and autoimmune adrenal insufficiency were excluded. Results The median age of 13 cases (12 males, 1 female) was 3 years and 10 months. Medical history or clinical manifestations on the first visit included hyperpigmentation, electrolyte imbalance/salt-wasting crisis, gastrointestinal symptoms, and fatigue, etc. All developments of external genitalia were normal. All cases presented with decreased serum cortisol and increased ACTH levels. Some of the cases showed decreased aldosterone level and plasma renin activity, while 17α-hydroxyprogesterone, testosterone, and androstenedione were in the normal range. Part of cases revealed delayed bone age and adrenal atrophy. Three gene mutations were detected in 13 patients, including NR0B1 gene (9/13), ABCD1 gene (3/13), and CYP11A1 gene (1/13). NR0B1, and ABCD1 gene mutations were pathogenic mutations, consistent with clinical characteristics. CYP11A1 gene mutation was heterozygote, which cannot fully explain the clinical features. Conclusion PAI in childhood presents common clinical manifestations of adrenal insufficiency, e. g. hyperpigmentation and electrolyte imbalance/salt-wasting crisis, but without specificity. Gene mutational analysis is necessary for precise diagnosis and prognosis estimation. NR0B1 and ABCD1 gene mutations were common in childhood with rare causes of PAI. Key words: Primary adrenal insufficiency; NR0B1 gene; Mutation; Children

Doença de Addison – a dificuldade de diagnóstico

Introduction: Primary adrenal insufficiency is a rare disease, especially in pediatric age. Case report: We report the case of a teenager with astenia with four months’ evolution, causing repeated visits to the emergency department during the previous month due gastrointestinal symptoms and a ten kilograms weight loss. In admission the patient had a reasonable general condition, hydrated and without cutaneous hyperpigmentation. Laboratory results showed hyponatremia, increased levels of corticotropin with normal cortisol levels, increased levels of renin with decreased aldosterone levels and presence of antissuprarrenal antibodies, allowing the diagnosis of autoimmune primary adrenal insufficiency. The boy started treatment with hydrocortisone and fludrocortisone with favorable response. Discussion/conclusions: The diagnosis of Addison’s disease requires a high degree of suspicion due its unspecific symptomatology. This disease often presents gastrointestinal symptoms. Thus, towards a patient with hyponatremia accompanied by constitutional and gastrointestinal symptoms, we must always consider this diagnosis.

Adipocytes, aldosterone and obesity-related hypertension.

Understanding the mechanisms linking obesity with hypertension is important in the current obesity epidemic as it may improve therapeutic interventions. Plasma aldosterone levels are positively correlated with body mass index and weight loss in obese patients is reported to be accompanied by decreased aldosterone levels. This suggests a relationship between adipose tissue and the production/secretion of aldosterone. Aldosterone is synthesized principally by the adrenal glands, but its production may be regulated by many factors, including factors secreted by adipocytes. In addition, studies have reported local synthesis of aldosterone in extra-adrenal tissues, including adipose tissue. Experimental studies have highlighted a role for adipocyte-secreted aldosterone in the pathogenesis of obesity-related cardiovascular complications via the mineralocorticoid receptor. This review focuses on how aldosterone secretion may be influenced by adipose tissue and the importance of these mechanisms in the context of obesity-related hypertension.

Aldosterone changes after consumption of a sodium-bicarbonated mineral water in humans. A four-way randomized controlled trial

Abnormally high aldosterone levels are associated to hypertension and cardiovascular disease. A sodium-rich mineral water was previously shown to reduce several markers of cardiovascular risk and did not increase blood pressure in healthy adults. We aimed to study the effects of consuming the same mineral water compared to a control water on aldosterone levels, and if the effects vary due to the presence of meal in healthy adults. The design was a four-way randomized controlled crossover 120-min-postprandial trial. Twenty-one healthy men and women participated in the study. Exclusion criteria are diabetes, hypertension, and being a usual consumer of carbonic mineral water. Two different mineral waters, high-sodium and bicarbonate mineral water (BW, sodium, 1g/L; bicarbonate, 2g/L) and low-mineral content control water (CW), were consumed with or without a standard meal (500mL per meal). Statistical analysis was performed by repeated measures ANOVA. The results are as follows: serum sodium did not vary, and serum potassium decreased throughout the assay (p = 0.01) without water influence. Consumption of BW significantly decreased aldosterone levels at 30 (p = 0.046), 60 (p = 0.009), and 120 (p = 0.025) min when consumed alone, and at 120min (p = 0.019) when consumed with meal, compared to CW. Moreover, the effect of BW on aldosterone levels was significant in women but not in men. In conclusion, consumption of a sodium-bicarbonated mineral water, in presence or absence of meal, induces aldosterone inhibition in healthy women, which is suggested to be a physiological response that protects them against hypertension. This trial is registered at clinicaltrial.gov as NCT01334840.

Obesity, hypertension and aldosterone: is leptin the link?

Obesity is a serious health hazard with rapidly increasing prevalence in the United States. In 2014, the World Health Organization estimated that nearly 2 billion people worldwide were overweight with an estimated 600 million of these obese. Obesity is associated with many chronic diseases, including cardiovascular disease and hypertension. Data from the Framingham Heart study suggest that approximately 78% of the risk for hypertension in men and 65% in women is related to excess body weight, a relationship that is further supported by studies showing increases in blood pressure with weight gain and decreases with weight loss. However, the exact mechanism by which excess body fat induces hypertension remains poorly understood. Several clinical studies have demonstrated elevated plasma aldosterone levels in obese individuals, especially those with visceral adiposity, with decreased aldosterone levels measured in concert with reduced blood pressure following weight loss. Since aldosterone is a mineralocorticoid hormone that regulates blood volume and pressure, serum aldosterone levels may link obesity and hypertension. Nevertheless, the mechanism by which obesity induces aldosterone production is unclear. A recent study by Belin de Chantemele and coworkers suggests that one adipose-released factor, leptin, is a direct agonist for aldosterone secretion; other adipose-related factors may also contribute to elevated aldosterone levels in obesity, such as very low-density lipoprotein (VLDL), the levels of which are elevated in obesity and which also directly stimulates aldosterone biosynthesis. This focused review explores the possible roles of leptin and VLDL in modulating aldosterone secretion to underlie obesity-associated hypertension.

Genomic and proteomic analysis of the inhibition of synthesis and secretion of aldosterone hormone induced by quinocetone in NCI-H295R cells.

Quinoxaline 1,4-dioxides (QdNOs) are widely used as a kind of antibacterial growth promoter in animal husbandry. The adrenal cortex was found to be one of the main toxic targets of QdNOs, accompanied by a decreased aldosterone level. However, the way in which QdNOs decrease production of the hormone aldosterone is far from clear. To illustrate the mechanism by which QdNOs damage the adrenal cortex and decrease aldosterone hormone levels, the QdNOs were screened to choose the drug with most toxic effects on aldosterone production, and then to reveal the mechanism between the gene and protein profiles in human adrenocortical cells (NCI-H295R cells). The results found that quinocetone (QCT) showed the highest adrenal toxic effect among QdNOs. After exposing H295R cells to 10 and 20μM QCT for 24h, compared with blank cells, the gene and protein expression profiles obtained were analyzed by microarray and MALDI TOF/TOF mass spectrometry, respectively. The results of microarray analysis suggested that ABCG1 and SREBF1, which were involved in the cholesterol biosynthetic and metabolic processes, and CYP17A1, NR4A2 and G6PD, which were related to aldosterone biosynthesis, were important molecular targets. It has been speculated that PKC and ERK pathways might be involved in the reduction of aldosterone production caused by QCT, through enhanced mRNA expression of CYP17A1. Additionally, JNK and p38MAPK signal transduction pathways might participate in apoptosis induced by QCT. Twenty-nine and 32 protein spots were successfully identified when cells were treated with 10 and 20μM QCT, respectively. These identified proteins mainly included material synthesis and energy metabolism-related proteins, transcription/translation processing-related proteins, signal transduction proteins, cytoskeletal proteins, molecular chaperones, proteins related to response to stress, and transport proteins. Further investigations suggested that oxidative stress caused by QCT was exacerbated through disruption of the Keap1/Nrf2/ARE anti-oxidative stress pathway. Taken together, the data demonstrated for the first time that the Keap1/Nrf2/ARE pathway plays a crucial role in adrenal toxicity, and that CYP17A1 was the key switch to reduce the aldosterone production induced by QCT. Furthermore, large numbers of genes and proteins and entry points for research in the inhibition of aldosterone synthesis induced by QCT were offered, which will provide new insight into the adrenal toxicity of QdNOs and help to provide a theoretical foundation for the formulation of safety controls for products obtained from animals and to design new QdNOs with less harmful effects.

Does continuous positive airway pressure reduce aldosterone levels in patients with obstructive sleep apnea?

Aldosterone is associated with the development of obstructive sleep apnea (OSA) and cardiovascular diseases. Continuous positive airway pressure (CPAP) is an effective treatment for OSA, but the impact of CPAP therapy on aldosterone levels in patients with OSA remains unclear. To address this issue, a meta-analysis was conducted to evaluate the effects of CPAP therapy on serum aldosterone levels in OSA. Two reviewers independently searched PubMed, Cochrane library, Embase, and Web of Science before March 2015. Information on characteristics of subjects, study design, and pre- and post-CPAP treatment of serum aldosterone was extracted for analysis. Standardized mean difference (SMD) was calculated to estimate the treatment effects of CPAP therapy. A total of 5 studies involving 329 patients were pooled into this meta-analysis, including 3 observational studies and 2 randomized controlled studies. Results indicated significantly decreased aldosterone levels after CPAP therapy (SMD = -0.236, 95% confidence interval (CI) = -0.45 to -0.02, z = 2.12, p = 0.034). This meta-analysis suggested that CPAP therapy was associated with a decrease in serum aldosterone in patients with OSA. Further large-scale, well-designed interventional investigations are needed to clarify this issue.

Angiotensin II type 1 receptor autoantibody as a novel regulator of aldosterone independent of preeclampsia.

Preeclamptic women and their infants have significant morbidity and mortality worldwide. Abnormal aldosterone signaling is involved in the pathogenesis of preeclampsia, and the presence of agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA) during disease has been observed. The role of AT1-AA in aldosterone generation with or without disease and the long-term impact of AT1-AA circulation in blood remain unclear. We therefore assessed circulating AT1-AA and aldosterone levels in 76 patients with preeclampsia (35 severe and 41 mild), 26 patients with gestational hypertension, and 50 normotensive healthy pregnant women. First, the correlation of AT1-AA levels was confirmed for preeclamptic patients. We report here that all AT1-AA-positive hypertensive pregnant women exhibited decreased aldosterone levels, and early-onset preeclampsia patients with high proteinuria showed an inverse correlation of aldosterone levels with AT1-AA. To study this effect in more detail, we confirmed that AT1-AA decreased aldosterone levels in pregnant rats and then demonstrated that aldosterone levels decreased in response to the chronic administration of AT1-AA into nonpregnant rats. These results suggested that AT1-AA regulates levels of aldosterone, which was tested with cell culture studies, revealing that activation of AT1 receptors by AT1-AA directly led to abnormal aldosterone generation in a time and dose-dependent manner. We present here a mechanism for regulation of aldosterone production: AT1-AA activates AT1 receptors on adrenocortical cells independent of pregnancy, in a time and dose-dependent manner.

Resistant hypertension—complex mix of secondary causes and comorbidities

Resistant hypertension—complex mix of secondary causes and comorbidities

Renin knock out modulates sodium reabsorption in the Dahl salt‐sensitive rats

Dahl salt‐sensitive (SS) rats fed a high salt diet exhibit increased blood pressure and renal damage. We have shown recently that ENaC expression and activity were significantly enhanced in SS rats fed a high salt diet. The renin‐angiotensin‐aldosterone system (RAAS) regulates blood pressure and water electrolyte homeostasis, and renin is a critical component of this system. Ren−/− rats were used to further investigate the role of the renin and RAAS in regulation of sodium transport in salt‐sensitive hypertension. Knock out rats were created using zinc‐finger nucleases designed to target the renin gene in the SS rat. As it has been shown previously, Ren−/− rats have lower body weight and blood pressure whereas no difference is observed in plasma and urine Na+ concentration compared to WT littermates. Here we demonstrate that aldosterone level is significantly lower in Ren−/− rats compared to WT littermates. Aldosterone level is also suppressed in SS rats fed high salt diet compared to animals fed low salt. Single‐channel patch clamp analysis of the freshly isolated collecting ducts revealed decreased ENaC activity in Ren−/− rats. Expression of ENaC subunits was also assessed by immunohistochemistry and Western blotting. We conclude that renin knock out causes low blood pressure, decrease in aldosterone level and suppression of ENaC activity in the aldosterone‐sensitive distal nephron. Supported by AHA, ADA and NIH.

Effects of Candesartan on Left Ventricular Function, Aldosterone and BNP in Chronic Heart Failure

PURPOSE: Heart failure (HF) is characterized by activation of neurohormonal systems such as aldosterone and natriuretic peptides. In the absence of published data, CandHeart trial was designed to assess the effects on left ventricular (LV) function, aldosterone and brain natriuretic peptide (BNP) of candesartan in patients with HF and preserved (LVEF ≥ 40%) or depressed (LVEF <40%) LV systolic function. METHODS: A total of 514 patients with stable symptomatic NYHA II-IV HF and any left ventricular ejection fraction (LVEF)were randomized to candesartan (target dose 32mg once daily) as add-on therapy or standard medical therapy alone. Standardized echocardiographic exams were performed locally under central quality control, whereas biomarkers were assayed in a core laboratory. RESULTS: The majority of patients (73.3%) were NYHA II and on ACE inhibitors (91.8%) and beta-blockers (85.4%). Mean age was 66 ± 11years. Mean LVEF was 36.2 ± 9.7% and 24.9% of patients had LVEF ≥ 40%. LVEF increased significantly more in the candesartan group (p = 0.09 at 12weeks and p = 0.01 at 48weeks) and left ventricular end-diastolic diameter decreased in candesartan group (p = 0.05 at 12weeks). Candesartan significantly reduced aldosterone at 48weeks (p = 0.009). BNP was reduced similarly over time in both study groups (p = 0.35 and p = 0.98 at 12 and 48weeks, respectively). There were 6.6% of discontinuations of candesartan for adverse events. CONCLUSIONS: In CandHeart, the addition of candesartan to standard medical treatment did not reduce circulating BNP more than standard therapy (primary endpoint), but it significantly improved LV function and produced a marked decrease in aldosterone levels at study end.

Abstract 17119: Renal Sympathetic Denervation Using an “Off-the-Shelf” Irrigated Radiofrequency Ablation Catheter for the Management of Drug-Resistant Hypertension

Introduction: Catheter-based renal sympathetic denervation using a specialized radiofrequency (RF) ablation catheter has recently been demonstrated to achieve sustained BP lowering in drug-refractory hypertension (HTN) pts. In theory, this non-irrigated RF ablation catheter has the potential to cause char formation at the point of catheter-tissue contact. We studied whether the same saline-irrigated RF ablation catheters used for ablation at other cardiovascular sites, which in theory would minimize the thromboembolic risk related to ablation itself, can safely provide similar BP reduction in refractory HTN pts. Methods: Ten pts with drug-resistant HTN (7±1 anti-hypertensive drugs/pt) underwent bilateral renal denervation with a standard saline-irrigated RF ablation catheter. Ambulatory BP recordings (24-hr) were obtained at baseline, and 1, 3, and 6 months post-procedure. In 5 pts, pre- and post-procedural measures of renal sympathetic activity were assessed, including plasma aldosterone, metanephrine, normetanephrine and plasma renin activity. All pts underwent follow-up renal angiography (at 1-5 months) to assess for renal artery (RA) stenosis. Results: Over a 6 month period, 1) the mean change in systolic/diastolic BP was -28/-20 mmHg; 2) all patients experienced a decrease in systolic BP of at least 10 mm Hg (range: 10-32 mm Hg); 3) there was no evidence of RA stenosis or aneurysm at repeat angiography; and 4) there was a significant decrease in renal sympathetic activity at 3 months: including metanephrine (-12±4, p=0.003) and normetanephrine (-17±4, p=0.0008) levels. There was also a significant decrease in aldosterone levels (-60±33 ng/l, p=0.02). Changes in the remaining variables were not significant: plasma renin activity (0.2 mg/l/hod, p=0.4), serum creatinine (-1 mmol/L, p=0.4); renin (0.3 mg/l/hod, p=0.4). Conclusions: Renal sympathetic denervation can be performed safely and effectively in pts with resistant hypertension using a standard saline-irrigated ablation catheter. Randomized placebo-controlled trials remain necessary to rule out a biofeedback-mediated placebo effect.

Percutaneous renal denervation for the treatment of resistant essential hypertension; the first Dutch experience

BackgroundIn a subpopulation of patients with essential hypertension, therapeutic targets are not met, despite the use of multiple types of medication. In this paper we describe our first experience with a novel percutaneous treatment modality using renal artery radiofrequency (RF) ablation.MethodsPatients who were resistant to at least three types of antihypertensive medical therapy (office systolic blood pressure ≥ 160 mmHg; n = 9) or who did not tolerate medication (n = 2) were selected. Between July and November 2010, a total of 11 patients received percutaneous RF treatment. Patients were followed up for 1 month after treatment. Urine and blood samples were taken to evaluate the effects on renal function and neurohumeral factors.ResultsNo periprocedural complications or adverse events during follow-up were noted. A reduction of mean office blood pressure was seen from 203/109 ± 32/19 mmHg at baseline to 178/97 ± 28/21 mmHg at 1 month follow-up (mean difference 25 ± 12 mmHg, p < 0.01). Also, we noted a significant decrease in aldosterone level (391 ± 210 pmol/L versus 250 ± 142 pmol/L; p = 0.03), while there was no decrease in plasma renin activity (190 ± 134 fmol/L/s versus 195 ± 163 fmol/L/s; p = 0.43). No change in renal function was noted.ConclusionCatheter-based renal denervation seems an attractive novel minimally invasive treatment option in patients with resistant hypertension, with a low risk of serious adverse events.