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Hypertension is associated with increased risk of cardiovascular disease and death. Evidence suggests that Mg2+ depletion contributes to hypertension. It is estimated that 25% or more of the United States population experiences chronic, latent Mg2+ depletion. This review explores mechanisms by which Mg2+ influences blood pressure, modifying risk of hypertension and complicating its treatment. Mechanisms addressed include effects upon i) sympathetic tone, via the modulation of N-methyl-D-aspartate (NMDA) receptor and N-type Ca2+ channel activity, influencing catecholamine release from sympathetic nerve endings; ii) vascular tone, via alteration of L-type Ca2+ and endothelial nitric oxide synthase (eNOS) activity and prostacyclin release; iii) renal K+ handling, influencing systemic K+ balance and potentially indirectly influencing blood pressure; iv) aldosterone secretion from the adrenal cortex; and v) modulation of pro-hypertensive inflammatory processes in dendritic cells and macrophages, including activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and stimulation of isolevuglandin (IsoLG) production. Discovery of these mechanisms has furthered our understanding of the pathogenesis of hypertension, with implications for treatment and has highlighted the role of Mg2+ balance in hypertension and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Overactivation of renin-aldosterone-angiotensin system (RAS) is part of the pathogenesis of obesity-associated hypertension. Evidences have shown that weight loss can result in reduction in blood pressure and RAS. This study was aim to investigate changes of plasma aldosterone concentration (PAC) after bariatric surgery. Methods: A prospective study was done in 14 morbidly obese patients undergoing bariatric surgery. Patients who were taking medications that can interfere with PAC and renin levels were excluded. Collection of blood samples were done at baseline and at 3 and 6-month post-bariatric surgery. Results: Four out of 14 patients had hypertension at baseline. Mean body mass index (BMI) was 56.7 ± 13.5 kg/m2. PAC were significantly decreased at 3-and 6-month post-bariatric surgery from 14.3 ± 8.0 to 7.5 ± 5.5 [reduction of 36% from baseline (P < 0.01)] and 8.0 ± 6.6 ng/dl [reduction of 32% from baseline (P < 0.05)] respectively. The reduction of PAC at 3-month post-surgery was correlated with the reduction of body weight (r = 0.46, P < 0.05), waist circumference (r = 0.73, P < 0.05) and percent of body fat (r = 0.58, P < 0.05). Conclusions: Maximal reduction of PAC in obese patients underwent bariatric surgery occurred during the first 3 months after bariatric surgery. The reduction of PAC was associated with the reduction of body weight, waist circumference and percent of body fat suggesting the link between RAS and obesity-mediated hypertension. [ABSTRACT FROM AUTHOR]

Background: Five guideline-recommended medication categories are available to treat patients who have heart failure (HF) with reduced ejection fraction. However, adherence to these medications is often suboptimal, which places patients at increased risk for poor health outcomes, including hospitalization. We aimed to examine the association between adherence to these medications and potentially preventable HF hospitalizations among younger insured adults with newly diagnosed HF. Methods and results: Using the 2008–2012 IBM MarketScan Commercial database, we followed 26,439 individuals aged 18–64 years with newly diagnosed HF and calculated their adherence (using the proportion of days covered (PDC) algorithm) to the five guideline-recommended medication categories: angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers; beta blockers; aldosterone receptor antagonists; hydralazine; and isosorbide dinitrate. We determined the association between PDC and long-term preventable HF hospitalizations (observation years 3–5) as defined by the United States (U.S.) Agency for Healthcare Research and Quality. Overall, 49.0% of enrollees had good adherence (PDC≥80%), which was more common among enrollees who were older, male, residing in higher income counties, initially diagnosed with HF in an outpatient setting, and who filled prescriptions for fewer medication categories assessed. Adherence differed by medication category and was lowest for isosorbide dinitrate (PDC = 60.7%). In total, 7.6% of enrollees had preventable HF hospitalizations. Good adherers, compared to poor adherers (PDC<40%), were 15% less likely to have a preventable hospitalization (HR 0.85, 95% confidence interval, 0.75–0.96). Conclusion: We found that approximately half of insured U.S. adults aged 18–64 years with newly diagnosed HF had good adherence to their HF medications. Patients with good adherence, compared to those with poor adherence, were less likely to have a potentially preventable HF hospitalization 3–5 years after their initial diagnosis. Because HF is a chronic condition that requires long-term management, future studies may want to assess the effectiveness of interventions in sustaining adherence. [ABSTRACT FROM AUTHOR]

Esports, or competitive video gaming, has rapidly increased in online play and viewing. The popularity of esports such as League of Legends may derive in part because it features skills-based coalitional competition. Whereas a sizable literature focuses on adult human hormones and competition, little research has addressed the hormone responses of men playing video games. The purpose of the present study is to investigate the effects of playing a coalitionary-based esport on young U.S. men's steroid hormone levels in a naturalistic study. We tested salivary steroid changes in response to esports club members (n = 26) playing League of Legends against other people and the computer. We hypothesized that esports competition would increase testosterone, cortisol, DHEA and androstenedione levels, with more pronounced increases in winners than losers. Participants provided saliva samples before and after competitions lasting 15–27 min in duration. Salivary testosterone, cortisol, DHEA and androstenedione levels did not change overall or between play against people vs. the computer or with respect to winning or losing. However, play duration (range 16–27 min) was positively related to changes in DHEA, androstenedione and testosterone during play against people. Aldosterone levels decreased overall. We suggest that the informal and familiar environment as well as relatively short play duration help account for generally null findings. These findings help document physiological effects of esport play, in turn contributing to a richer understanding of why so many play and watch esports. [ABSTRACT FROM AUTHOR]

Background To promote ideal cardiovascular health, the American Heart Association recommends adhering to Life's Simple 7 (LS7)-achieving healthy targets for body mass index, physical activity, dietary intake, blood pressure, fasting plasma glucose, and cholesterol, along with smoking abstinence. Poorer achievement of LS7 (lower score) has been associated with the development of hypertension and cardiovascular disease. However, less is known about the associations between LS7 and specific biomarkers linked to cardiovascular health: aldosterone, CRP (C-reactive protein), and IL-6 (interleukin-6). Methods and Results We analyzed 379 individuals (age 18-66 years) from the HyperPATH (International Hypertensive Pathotype), who were maintained on ≥200 mEq of sodium daily for 1 week. We calculated a 14-point summative LS7 score according to participants' baseline data. Based on the range of LS7 score in this population (3-14), we classified participants as "inadequate" (3-6), "average" (7-10), and "optimal" (11-14). Regression analyses found that a higher LS7 score group was associated with lower levels of serum and urinary aldosterone ( P trend <0.001 and P <0.001), and a blunted increase in serum aldosterone with angiotensin II infusion ( trend =0.001, respectively), lower plasma renin activity ( P trend =0.001). Conclusions A higher LS7 score was associated with a lower activity of the renin-angiotensin-aldosterone system and lower levels of the inflammatory markers CRP and IL-6. These findings offer a possible link between ideal cardiovascular health targets and biomarkers known to play a central role in the development of cardiovascular disease.P trend =0.023). Being in the "optimal" LS7 score group was associated with lower serum CRP ( P trend =0.001) and IL-6 ( P trend =0.001). Conclusions A higher LS7 score was associated with a lower activity of the renin-angiotensin-aldosterone system and lower levels of the inflammatory markers CRP and IL-6. These findings offer a possible link between ideal cardiovascular health targets and biomarkers known to play a central role in the development of cardiovascular disease.

Prognostic effect of discontinuing renin-angiotensin-aldosterone-system-inhibitor (RAASi) for patients with heart failure (HF) after acute myocardial infarction (AMI) whose left ventricular (LV) systolic function was restored during follow-up is unknown. To investigate the outcome after discontinuing RAASi in post-AMI HF patients with restored LV ejection fraction (EF). Of 13,104 consecutive patients from the nationwide, multicenter, and prospective Korea Acute Myocardial Infarction-National Institutes of Health (KAMIR-NIH) registry, HF patients with baseline LVEF < 50% that was restored to ≥ 50% at 12-month follow-up were selected. Primary outcome was a composite of all-cause death, spontaneous MI, or rehospitalization for HF at 36-month after index procedure. Of 726 post-AMI HF patients with restored LVEF, 544 maintained RAASi (Maintain-RAASi) beyond 12-month, 108 stopped RAASi (Stop-RAASi), and 74 did not use RAASi (RAASi-Not-Used) at baseline and follow-up. Systemic hemodynamics and cardiac workloads were similar among groups at baseline and during follow-up. Stop-RAASi group showed elevated NT-proBNP than Maintain-RAASi group at 36-month. Stop-RAASi group showed significantly higher risk of primary outcome than Maintain-RAASi group (11.4% vs. 5.4%; adjusted hazard ratio [HR adjust ] 2.20, 95% confidence interval [CI] 1.09-4.46, P = 0.028), mainly driven by increased risk of all-cause death. The rate of primary outcome was similar between Stop-RAASi and RAASi-Not-Used group (11.4% vs. 12.1%; HR adjust 1.18 [0.47-2.99], P = 0.725). In post-AMI HF patients with restored LV systolic function, RAASi discontinuation was associated with significantly increased risk of all-cause death, MI, or rehospitalization for HF. Maintaining RAASi will be necessary for post-AMI HF patients, even after LVEF is restored., (© 2023. The Author(s).)

Background: Different renin-angiotensin-aldosterone system inhibitor (RAASI) usage patterns exist among patients undergoing lower extremity bypass (LEB) for peripheral arterial disease. We studied the association of RAASI usage patterns with LEB outcomes to determine which pattern is associated with improved survival after LEB., Methods: We evaluated peripheral arterial disease patients who underwent LEB between January 2014 and December 2018 in the Vascular Quality Initiative-Medicare matched database. Study cohorts included no RAASI use, preoperative RAASI use only, postoperative RAASI use only, and continuous RAASI use both preoperatively and postoperatively. Logistic and Cox regression was used to adjust for potential confounders. Primary outcome was 2-year amputation-free survival (AFS)., Results: Of 19,012 patients included, 1,574 (8.3%) were on RAASIs preoperatively only, 1,051 (5.5%) postoperatively only, and 8,484 (45.2%) continuously. Compared to no RAASI use, isolated preoperative RAASI use was associated with 2.8-fold increased odds of 30-day mortality (adjusted Odds Ratio, 2.75; 95% confidence interval [CI], 2.15-3.51; P < 0.001) whereas continuous RAASI use had 56% lower odds of 30-day mortality (adjusted Odds Ratio, 0.44; 95% CI, 0.34-0.58; P < 0.001). Two-year AFS was 63.2% for no RAASI use and 60.4%, 66.2%, and 73.4% for preoperative, postoperative, and continuous RAASI use, respectively (P < 0.001). While no RAASI use and postoperative RAASI use had comparable adjusted risks of 2-year major amputation or death (adjusted Hazard Ratio [aHR], 0.94; 95% CI, 0.83-1.06; P = 0.312), this risk was 14% higher for preoperative RAASI use only (aHR, 1.14; 95% CI, 1.04-1.26; P = 0.006) and 23% lower for continuous RAASI use (aHR, 0.77; 95% CI, 0.72-0.82; P < 0.001)., Conclusions: Isolated preoperative RAASI use was associated with worse 30-day mortality and 2-year AFS, while continuous RAASI use was associated with improved 30-day mortality and 2-year AFS. Optimum survival benefit may be derived from continuous RAAS inhibition in the preoperative and postoperative periods., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The average salt intake of people in Canada, the United States, and Europe is about 3,400mg of sodium per day, which exceeds the recommended intake levels set by various health organizations. The World Health Organization recommends a worldwide reduction of sodium intake to less than 2,000mg per day. Most research to date has focused on the negative effects of high-sodium intake; however, little information is available on the metabolic effects of low-sodium intakes. This review focuses on the hormonal changes associated with low-sodium diets, specially the hormones involved in metabolism and cardiovascular and renal function. Based largely on rodent studies, low-sodium diets have been associated with changes in glycemic control, energy metabolism, cardiovascular disease risk, cholesterol concentrations, inflammation, and functioning of the renin-angiotensin-aldosterone system. Overall, research has revealed mixed results regarding the impact of dietary sodium intake on various hormones. Further research is required to assess the effects of sodium reduction on hormones and their associated pathways in order to determine the likelihood of any unintended effects. [ABSTRACT FROM AUTHOR]

BACKGROUND Although variations in plasma renin activity (PRA) and aldosterone have been examined in whites and blacks, the association of these hormones with blood pressure in multiethnic populations has not been described. METHODS We measured PRA and aldosterone in 1,021 participants in the Multi-Ethnic Study of Atherosclerosis not taking antihypertensives and examined the association between ethnicity and PRA/aldosterone and the association between PRA/aldosterone with systolic blood pressure (SBP). RESULTS Average age was 62 (SD = 9) years, and 49% of participants were women. Median PRA was 0.51 (interquartile range (IQR) = 0.29–0.87) ng/ml/hour, and median aldosterone was 12.6 (IQR = 9.1–17.1) ng/dl. After age and sex adjustment, compared with whites, blacks had 28% lower PRA and 17.4% lower aldosterone, and Hispanics had 20.1% higher PRA but similar aldosterone levels. After multivariable adjustment, compared with whites, only Hispanic ethnicity independently associated with higher PRA (0.18ng/ml/hour; 95% confidence interval (CI) = 0.06–0.31). Blacks had lower aldosterone (−1.7ng/dl; 95% CI = −3.2 to −0.2) compared with whites. After multivariable adjustment, PRA was associated with lower SBP in whites (−3.2mm Hg; 95% CI = −5.2 to −1.2 per standardized unit PRA), Chinese (−3.5mm Hg; 95% CI = −6.2 to −0.80 per standardized unit), and Hispanics (−2.3mm Hg; 95% CI = −4.1 to −0.6 per standardized unit) but not blacks. Aldosterone was associated with higher SBP only in Hispanics (2.5mm Hg; 95% CI = 0.4–4.5 per SD). CONCLUSIONS Compared with whites, blacks have lower aldosterone and Hispanics have higher PRA. Aldosterone had significant associations with higher SBP in Hispanics compared with other groups, a finding that may suggest a different mechanism of hypertension. [ABSTRACT FROM AUTHOR]

Purpose: Adrenalectomies performed for the treatment of primary aldosteronism due to unilateral adenoma are traditionally confirmed with, and guided by, results from adrenal vein sampling (AVS). However, the usefulness of AVS at the expense of cost and complications is debated, and many institutions have independent protocols that use AVS to varying degrees., Methods: Cost-effectiveness of AVS- vs computed tomography (CT)-based adrenalectomy was calculated using decision tree models. The tree was populated with values describing biochemical post-operative outcomes from the published literature; patients were placed into AVS- or CT-dependent treatment arms. Biochemical outcomes were defined based on patients' potassium levels and aldosterone-renin ratios. Patients underwent adrenalectomies and received medical management dosed based on surgical outcomes. Costs were represented by Medicare (FY2021) reimbursement rates (US$) and quality-adjusted life-years (QALYs) were calculated using published morbidity and survival data. A willingness-to-pay of $100,000 per QALY gained was set to determine the most cost-effective strategy. The primary outcome was the incremental cost-effectiveness ratio (ICER) associated with biochemical outcomes., Results: The base case analyses favored the use of AVS-guided care, which cost $307.65 more but yielded 0.78 more QALYs, resulting in an ICER of $392.57. These results were upheld by all one-way and two-way sensitivity analyses. In 100,000 random-sampling simulations, AVS-guided care was favored 100% of the time., Conclusions: For patients with primary aldosteronism receiving adrenalectomies with curative intent, the more cost-effective method based on biochemical outcomes is AVS-based care. Recent literature suggests biochemical resolution should be favored over clinical resolution, due to long-term detriments of increased aldosterone independent of clinical symptoms., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

BackgroundHypertension and obesity are highly prevalent among African Americans (AAs). We have previously reported that both plasma aldosterone (PA) and body mass index (BMI) are higher in hypertensive than in normotensive AAs. This study evaluates the relative contributions of adiposity and PA to hypertension in AAs.MethodsA total of 466 AAs (50% hypertensive, 51% women) were evaluated in a Clinical Research Center by stratifying them into three subgroups based on BMI (normal weight, overweight, and obese). Anthropometric measurements, ambulatory blood pressure (BP), fasting glucose, insulin, 24-h urine sodium and potassium, creatinine clearance, standing PA and plasma renin activity (PRA) were measured. Insulin resistance was estimated by the homeostasis model assessment.ResultsCompared to normotensives, hypertensives had higher BMI, waist circumference (WC), and were more insulin resistant (P ≤ 0.01). When stratified by BMI, hypertensives in each BMI strata had higher PA (P ≤ 0.05) and lower PRA (P ≤ 0.01) compared to normotensives. Compared to normotensives, WC was greater in overweight and obese hypertensives, but not in normal-weight hypertensives. In the overall sample, age, WC, PA, and PRA were the major contributors to BP variance and to hypertension. Among normal-weight subjects, PA and PRA significantly predicted BP and the odds ratio for hypertension, whereas WC had no predictive value.ConclusionsPA, but not WC, is associated with BP and likelihood of hypertension in normal-weight AAs, whereas both WC and PA are predictive of hypertension in overweight and obese individuals. This suggests that aldosterone antagonists may be useful for the treatment of hypertension among AAs, regardless of BMI.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.167 [ABSTRACT FROM AUTHOR]

The article discusses the study which evaluates the cardiac event prediction using cortisol levels in patients with chronic heart failure in the U.S. It notes that study compares the effects of cortisol in aldosterone (ALD), adrenocorticotropic hormone and brain natriuretic peptide (BNP) and the impact of oxidative stress. It concludes that serum cortisol were complementary and incremental cardiac event risk predictor provided that it is combined with BNP in patients with HF.

The article presents study on the effect of androgen on the plasma levels of androstenedione and aldosterone among goats in the U.S. Study shows that plasma cortisol (Cor) levels were increased by all adrenocortisotropic hormone (ACTH) injection doses. It was found out that plasma aldosterone levels were also increased and that there were no differences between cholesterol (cho)- and dihydrostestosterone (DHT) treated goats. However, the plasma aldosterone levels were restored rapidly only in cho-treated goats when they were given lower doses.

Increasing recognition of the role of aldosterone in cardiovascular disease has been supported by a significant body of evidence from animal models. This evidence has been translated into clinical practice, and large-scale, randomized, placebo-controlled trials have confirmed the beneficial effects of mineralocorticoid blockade in patients with heart failure. As a receptor antagonist in clinical practice that has prompted the search for a potent and specific antagonist without the sexual side effects of spironolactone. Eplerenone, a mineralcorticoid-receptor antagonist with minimal binding to the progesterone and androgen receptors, is now licensed for treatment of heart failure in Europe and heart failure and hypertension in the US; it has also been proposed as a treatment for a variety of cardiovascular conditions. This article reviews the current concepts of the actions of aldosterone at a cellular level. Recent findings regarding its role as a cardiovascular hormone, both in animal models and human studies, are discussed. We also describe the development of mineralocorticoid-receptor blockers following the isolation of aldosterone and discuss the subsequent search for a specific mineralcorticoid antagonist. In addition we detail the effects of eplerenone in a number of clinical situations and outline its potential future applications. [ABSTRACT FROM AUTHOR]

Explains the feature of liddle syndrome as a rare form of automosal dominant hypertension and cardiovascular sequelae in the United States. Actual rates of aldosterone excretion; Forms of renin hypertension; Deduction of amino acid sequence of the beta subunit.

The article investigates the production rates of aldosterone in manic-depressive psychotics in the U.S. The investigation is aimed at identifying the involvement of aldosterone in the reduction of residual sodium and exchangeable sodium in patients. It uses 2 subjects, one of which was used in a previously published study on similar discipline. The subjects' urine were examined for aldosterone and radio-activity was measured in a Packard liquid scintillation spectrometer. The results of the study indicates that aldosterone production rates were higher during mania than during depression. A discussion on the results of the study is offered.

Focuses on aldosterone receptor blocker eplerenone (Inspra) which was approved by the U.S. Food and Drug Administration for the improvement of the survival of patients with congestive heart failure (CHF) following an acute myocardial infarction. Information on eplerenone, a derivative of spironolactone; Clinical studies conducted in relation with eplerenone; Recommended dose for CHF through eplerenone therapy; Adverse effects in patients receiving the drug.

Context: Pathogenic variants in KCNJ5, encoding the GIRK4 (Kir3.4) potassium channel, have been implicated in the pathogenesis of familial hyperaldosteronism type-III (FH-III) and sporadic primary aldosteronism (PA). In addition to aldosterone, glucocorticoids are often found elevated in PA in association with KCNJ5 pathogenic variants, albeit at subclinical levels. However, to date no GIRK4 defects have been linked to Cushing syndrome (CS)., Patient: We present the case of a 10-year-old child who presented with CS at an early age due to bilateral adrenocortical hyperplasia (BAH). The patient was placed on low-dose ketoconazole (KZL), which controlled hypercortisolemia and CS-related signs. Discontinuation of KZL for even 6 weeks led to recurrent CS., Results: Screening for known genes causing cortisol-producing BAHs (PRKAR1A, PRKACA, PRKACB, PDE11A, PDE8B, ARMC5) failed to identify any gene defects. Whole-exome sequencing showed a novel KCNJ5 pathogenic variant (c.506T>C, p.L169S) inherited from her father. In vitro studies showed that the p.L169S variant affects conductance of the Kir3.4 channel without affecting its expression or membrane localization. Although there were no effects on steroidogenesis in vitro, there were modest changes in protein kinase A activity. In silico analysis of the mutant channel proposed mechanisms for the altered conductance., Conclusion: We present a pediatric patient with CS due to BAH and a germline defect in KCNJ5. Molecular investigations of this KCNJ5 variant failed to show a definite cause of her CS. However, this KCNJ5 variant differed in its function from KCNJ5 defects leading to PA. We speculate that GIRK4 (Kir3.4) may play a role in early human adrenocortical development and zonation and participate in the pathogenesis of pediatric BAH., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Background: Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease., Objective: To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure., Design: Cross-sectional study., Setting: 4 U.S. academic medical centers., Participants: Participants with normotension ( n  = 289), stage 1 hypertension ( n  = 115), stage 2 hypertension ( n  = 203), and resistant hypertension ( n  = 408)., Measurements: Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 μg/24 h., Results: Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 μg/24 h (95% CI, 5.2 to 7.7 μg/24 h) in normotension, 7.3 μg/24 h (CI, 5.6 to 8.9 μg/24 h) in stage 1 hypertension, 9.5 μg/24 h (CI, 8.2 to 10.8 μg/24 h) in stage 2 hypertension, and 14.6 μg/24 h (CI, 12.9 to 16.2 μg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism., Limitation: Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics., Conclusion: The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension., Primary Funding Source: National Institutes of Health.

Background Duchenne muscular dystrophy incurs nearly universal dilated cardiomyopathy by the third decade of life, preceded by myocardial damage and impaired left ventricular strain by cardiac magnetic resonance. It has been shown that (1) mineralocorticoid receptor antagonist therapy with spironolactone attenuated damage while maintaining function when given early in a mouse model and (2) low-dose eplerenone stabilized left ventricular strain in boys with Duchenne muscular dystrophy and evident myocardial damage but preserved ejection fraction. We hypothesized that moderate-dose spironolactone versus eplerenone would provide similar cardioprotection in this first head-to-head randomized trial of available mineralocorticoid receptor antagonists, the AIDMD (Aldosterone Inhibition in Duchenne Muscular Dystrophy) trial. Methods and Results This was a multicenter, double-blind, randomized, noninferiority trial. Subjects were randomized to eplerenone, 50 mg, or spironolactone, 50 mg, orally once daily for 12 months. The primary outcome was change in left ventricular systolic strain at 12 months. Among 52 enrolled male subjects, aged 14 (interquartile range, 12-18) years, spironolactone was noninferior to eplerenone (∆strain, 0.4 [interquartile range, -0.4 to 0.6] versus 0.2 [interquartile range, -0.2 to 0.7]; P =0.542). Renal and pulmonary function remained stable in both groups, and no subjects experienced serious hyperkalemia. Infrequent adverse events included gynecomastia in one subject in the spironolactone arm and facial rash in one subject in the eplerenone arm. Conclusions In boys with Duchenne muscular dystrophy and preserved left ventricular ejection fraction, spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354352.

Background: Increased resting heart rate is a risk factor for cardiovascular mortality and morbidity. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve cardiac sympathetic nerve activity, reduce heart rate and attenuate left ventricular remodelling. Whether or not the beneficial effects of MRA are affected by heart rate in heart failure patients with reduced ejection fraction (HFREF) is unclear., Methods: We undertook a secondary analysis of data from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study to assess if clinical outcomes, as well as the efficacy of eplerenone, varied according to heart rate at baseline., Results: High resting heart rate of 80 bpm and above predisposed patients to greater risk of all outcomes in the trial, regardless of treatment allocation. The beneficial effects of eplerenone were observed across all categories of heart rate. Eplerenone reduced the risk of primary endpoint, the composite of cardiovascular death and hospitalisation for heart failure, by 30% (aHR 0.70; 95% CI 0.54-0.91) in subjects with heart rate ≥ 80 bpm, and by 48% (aHR 0.52; 95% CI 0.33-0.81) in subjects with heart rate ≤ 60 bpm. Eplerenone also reduced the risks of hospitalisation for heart failure, cardiovascular deaths and all-cause deaths independently of baseline heart rate., Conclusions: Baseline heart rate appears to be an important predictor of major clinical outcome events in patients with HFREF, as has been previously reported. The benefits of eplerenone were preserved across all categories of baseline heart rate, without observed heterogeneity in the responses.

The Adrenal Cortex Meeting celebrated the awarding of the Keith L. Parker Award Lecture to William E. (Bill) Rainey, and this article reviews his training, career, and contributions to the field of adrenal biology., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Somatic mutations have been identified in aldosterone-producing adenomas (APAs) in genes that include KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Based on independent studies, there appears to be racial differences in the prevalence of somatic KCNJ5 mutations, particularly between East Asians and Europeans. Despite the high cardiovascular disease mortality of blacks, there have been no studies focusing on somatic mutations in APAs in this population. In the present study, we investigated genetic characteristics of APAs in blacks using a CYP11B2 (aldosterone synthase) immunohistochemistry-guided next-generation sequencing approach. The adrenal glands with adrenocortical adenomas from 79 black patients with primary aldosteronism were studied. Seventy-three tumors from 69 adrenal glands were confirmed to be APAs by CYP11B2 immunohistochemistry. Sixty-five of 73 APAs (89%) had somatic mutations in aldosterone-driver genes. Somatic CACNA1D mutations were the most prevalent genetic alteration (42%), followed by KCNJ5 (34%), ATP1A1 (8%), and ATP2B3 mutations (4%). CACNA1D mutations were more often observed in APAs from males than those from females (55% versus 29%, P=0.033), whereas KCNJ5 mutations were more prevalent in APAs from females compared with those from males (57% versus 13%, P<0.001). No somatic mutations in aldosterone-driver genes were identified in tumors without CYP11B2 expression. In conclusion, 89% of APAs in blacks harbor aldosterone-driving mutations, and unlike Europeans and East Asians, the most frequently mutated aldosterone-driver gene was CACNA1D. Determination of racial differences in the prevalence of aldosterone-driver gene mutations may facilitate the development of personalized medicines for patients with primary aldosteronism.

Aldosterone sensitivity, defined as the magnitude of the association of plasma aldosterone concentration with blood pressure (BP), seems to be a function of plasma volume. It increases as plasma renin activity decreases, and it is more significant in blacks but less so in whites. Age is a strong determinant of BP, and an increase in aldosterone sensitivity could contribute to the increase in BP. In the present study, we tested the hypothesis that aldosterone sensitivity increases with age. We used observational data collected from normotensive blacks and whites enrolled in a prospective cohort study. They were studied as children (248 blacks/357 whites) and again as young adults (74 blacks/125 whites) over an age range of 7 to 39 years. A varying-coefficient regression analysis was used to explore the influences of aldosterone on systolic BP. After controlling for body mass index, race, and sex, both plasma renin activity and plasma aldosterone concentration were lower in blacks, and their levels declined with age ( P <0.001). In blacks, plasma aldosterone concentration decreased 0.25 ng/dL per year; in whites, plasma aldosterone concentration decreased 0.18 per year. Aldosterone's effect on BP, characterized by a smooth function of age, intensified as age increased, especially in blacks ( P <0.01), suggesting an increased aldosterone sensitivity with age. In comparison to blacks, age-related changes in aldosterone sensitivity in whites were not statistically significant. These findings extend the rationale for targeting aldosterone in the treatment of hypertension, especially in blacks., (© 2018 American Heart Association, Inc.)

Background: In patients with heart failure and preserved ejection fraction (HF-PEF) randomized in the Americas as part of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, treatment with spironolactone enhanced the risk of hyperkalemia but reduced the risk of hypokalemia. We examined the clinical correlates and prognostic implications of incident hypo- and hyperkalemia during study follow-up., Methods: We defined the region-specific incidence of hypokalemia (potassium [K + ] <3.5 mmol/l) and hyperkalemia (K +  ≥5.5 mmol/l) among both placebo- and spironolactone-assigned patients in TOPCAT. Factors associated with incident hypokalemia and hyperkalemia and the relationship between incident K + abnormalities and the risk of subsequent mortality were analyzed in multivariable regression models restricted to the Americas., Results: In the Americas, assignment to spironolactone increased risk for hyperkalemia (hazard ratio 3.21, 95% confidence interval 2.46-4.20, P < .001) and reduced risk of hypokalemia (hazard ratio 0.43, 95% confidence interval 0.34-0.55, P < .001). Assignment to spironolactone, lower estimated glomerular filtration rate, higher baseline K + , diabetes, and lower hemoglobin were associated with incident hyperkalemia, whereas assignment to placebo, lower K + , younger age, lower estimated glomerular filtration rate, and use of diuretics at baseline were associated with hypokalemia. The combination of spironolactone and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was associated with incremental risk for hyperkalemia and protection from hypokalemia. Independent of region, both hypokalemia and hyperkalemia, were associated with higher risk for cardiovascular and all-cause mortality in multivariable-adjusted Cox regression models., Conclusions: Both hyperkalemia and hypokalemia are associated with heightened risk for mortality in HF-PEF. Use of spironolactone in this population requires careful laboratory surveillance of K + and creatinine, particularly in high-risk groups., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Focuses on the role of aldosterone blockade in managing heart failure. Social and economic impact of heart failure in the U.S.; Role of neurohormonal mediators in renin-angiotensin-aldosterone and sympathetic nervous system in heart failure.

The article presents some questions and answers with the aim of describing the social and economic impact of heart failure in the U.S. It explains the role of neurohormonal mediators of the renin-angiotensin-aldosterone and sympathetic nervous systems in heart failure, describes evidence that supports the need for direct aldosterone blockade to maintain decreased aldosterone concentrations in patients with heart failure and identify the role of diuretics, digoxin and angiotensin converting enzyme inhibitors in the treatment algorithm of heart failure. Moreover, the article explains the rationale and emerging strategies for using aldosterone receptor antagonists in the management of heart failure.

The article presents various studies on medical topics. One study examined the risk of obese individuals who get bariatric surgery in getting diabetes in the future. Another research assessed the association between body mass index and mortality in established type 2 diabetes. Plasma aldosterone was measured to examine its role as a biomarker of cardiorenal and metabolic disease.

We sought to investigate the role of aldosterone as a mediator of disease and its relationship with the counter-regulatory natriuretic peptide (NP) system. We measured plasma aldosterone (n=1674; aged≥45 years old) in a random sample of the general population from Olmsted County, MN. In a multivariate logistic regression model, aldosterone analyzed as a continuous variable was associated with hypertension (odds ratio [OR]=1.75; 95% confidence interval [CI]=1.57-1.96; P<0.0001), obesity (OR=1.34; 95% CI=1.21-1.48; P<0.0001), chronic kidney disease (OR=1.39; 95% CI=1.22-1.60; P<0.0001), central obesity (OR=1.47; 95% CI=1.32-1.63; P<0.0001), metabolic syndrome (OR=1.41; 95% CI=1.26-1.58; P<0.0001), high triglycerides (OR=1.23; 95% CI=1.11-1.36; P<0.0001), concentric left ventricular hypertrophy (OR=1.22; 95% CI=1.09-1.38; P=0.0007), and atrial fibrillation (OR=1.24; 95% CI=1.01-1.53; P=0.04), after adjusting for age and sex. The associations with hypertension, central obesity, metabolic syndrome, triglycerides, and concentric left ventricular hypertrophy remained significant after further adjustment for body mass index, NPs, and renal function. Furthermore, aldosterone in the highest tertile correlated with lower NP levels and increased mortality. Importantly, most of these associations remained significant even after excluding subjects with aldosterone levels above the normal range. In conclusion, we report that aldosterone is associated with hypertension, chronic kidney disease, obesity, metabolic syndrome, concentric left ventricular hypertrophy, and lower NPs in the general community. Our data suggest that aldosterone, even within the normal range, may be a biomarker of cardiorenal and metabolic disease. Further studies are warranted to evaluate a therapeutic and preventive strategy to delay the onset and progression of disease, using mineralocorticoid antagonists or chronic NP administration in high-risk subjects identified by plasma aldosterone., (© 2014 American Heart Association, Inc.)

The article discusses the findings of the study ONTARGET and TRANSCEND which examines the efficacy of renin-angiotensin-aldosterone system (RAAS) inhibition and blockade to reduce the mortality and morbidity rate of cardiovascular diseases in the U.S. It notes that the effectiveness of angiotensin converting enzyme inhibitors (ACEIs) with angiotensin receptor blocking agents has been studied. It relates that the effective strategy to prevent the effects of RAAS activation has been provided.

Sixty million Americans have hypertension, a major cardiovascular risk factor. Its presence accelerates the atherosclerotic process, producing strokes, heart attacks, heart failure, renal failure, and peripheral vascular disease. This article highlights the historical landmarks in the study of this disease from the first documented measurement of blood pressure in 1733, through the most recent pharmacologic approaches to treatment. In addition, the roles of the kidney and the renin-angiotensin-aldosterone system are examined.