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1.
[Antifibrotic renal role of mineralcorticoid receptor antagonists].
Ocello, A, La Rosa, S, Fiorini, F, Randone, S, Maccarrone, R, Battaglia, G, Granata, A
Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. 2019;(4)
Abstract
Cardiovascular and renal diseases are one of the main health problems in all industrialized countries. Their incidence is constantly increasing due to the aging of the population and the greater prevalence of obesity and type 2 diabetes. Clinical evidence suggests that aldosterone and the activation of mineralocorticoid receptors (MR) have a role in the pathophysiology of cardiovascular and renal diseases. Moreover, clinical studies demonstrate the benefits of mineralocorticoid receptor antagonists (MRAs) on mortality and progression of heart and kidney disease. In addition to renal effects on body fluid homeostasis, aldosterone has multiple extrarenal effects including the induction of inflammation, vascular rigidity, collagen formation and stimulation of fibrosis. Given the fundamental role of MR activation in renal and cardiac fibrosis, effective and selective blocking of the signal with MRAs can be used in the clinical practice to prevent or slow down the progression of heart and kidney diseases. The aim of the present work is to review the role of MRAs in light of the new evidence as well as its potential use as an antifibrotic in chronic kidney disease (CKD). The initial clinical results suggest that MRAs are potentially useful in treating patients with chronic kidney disease, particularly in cases of diabetic nephropathy. We don't yet have efficacy and safety data on the progression of kidney disease up to the end stage (ESRD) and filling this gap represents an important target for future trials.
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2.
Towards a circulating marker of hepato-visceral fat excess: S100A4 in adolescent girls with polycystic ovary syndrome - Evidence from randomized clinical trials.
Malpique, R, Sánchez-Infantes, D, Garcia-Beltran, C, Taxerås, SD, López-Bermejo, A, de Zegher, F, Ibáñez, L
Pediatric obesity. 2019;(5):e12500
Abstract
S100A4 is a marker of subcutaneous adipose tissue dysfunction. Polycystic ovary syndrome (PCOS) is often driven by hepato-visceral adiposity. PCOS phenotypes are normalized more by reduction of central fat with spironolactone/pioglitazone/metformin (SPIOMET) than by oral contraceptive (OC) treatment. We studied whether circulating S100A4 concentrations are high in adolescents with PCOS and, if so, whether they normalize more with OC or SPIOMET. Assessments included circulating S100A4, endocrine markers, body composition, abdominal fat partitioning in controls (n = 12) and girls with PCOS (n = 51; age 15.8 y; body mass index [BMI] 24.5 kg/m2 ), and 1-year changes in girls with PCOS randomized for OC (n = 27) or SPIOMET (n = 24) treatment. Mean S100A4 concentrations were 71% higher (P < 0.001) in girls with PCOS than in controls and associated with hepato-visceral adiposity (r = 0.47; P = 0.001); S100A4 concentrations decreased more (P < 0.01) with SPIOMET, those decreases associating to hepato-visceral fat loss (r = 0.50; P < 0.0001). S100A4 may become a circulating marker of hepato-visceral fat excess in adolescents with PCOS.
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3.
Real-World Associations of Renin-Angiotensin-Aldosterone System Inhibitor Dose, Hyperkalemia, and Adverse Clinical Outcomes in a Cohort of Patients With New-Onset Chronic Kidney Disease or Heart Failure in the United Kingdom.
Linde, C, Bakhai, A, Furuland, H, Evans, M, McEwan, P, Ayoubkhani, D, Qin, L
Journal of the American Heart Association. 2019;(22):e012655
Abstract
Background Dosing of renin-angiotensin-aldosterone system inhibitors (RAASi) may be modified to manage associated hyperkalemia risk; however, this approach could adversely affect cardiorenal outcomes. This study investigated real-world associations of RAASi dose, hyperkalemia, and adverse clinical outcomes in a large cohort of UK cardiorenal patients. Methods and Results This observational study included RAASi-prescribed patients with new-onset chronic kidney disease (n=100 572) or heart failure (n=13 113) first recorded between January 2006 and December 2015 in Clinical Practice Research Datalink and linked Hospital Episode Statistics databases. Odds ratios associating hyperkalemia and RAASi dose modification were estimated using logistic generalized estimating equations with normal (<5.0 mmol/L) serum potassium level as the reference category. Patients with serum potassium ≥5.0 mmol/L had higher risk of RAASi down-titration (adjusted odds ratios, chronic kidney disease: 1.79 [95% CI, 1.64-1.96]; heart failure: 1.33 [95% CI, 1.08-1.62]). Poisson models were used to estimate adjusted incident rate ratios of adverse outcomes based on total RAASi exposure (<50% and ≥50% of the guideline-recommended RAASi dose). Incidence of major adverse cardiac events and mortality was consistently higher in the lower dose group (adjusted incident rate ratios: chronic kidney disease: 5.60 [95% CI, 5.29-5.93] for mortality and 1.60 [95% CI, 1.55-1.66] for nonfatal major adverse cardiac events; heart failure: 7.34 [95% CI, 6.35-8.48] for mortality and 1.85 [95% CI, 1.71-1.99] for major adverse cardiac events). Conclusions The results of this real-world analysis highlight the potential negative impact of suboptimal RAASi dosing and the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation.
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4.
Effects of Mineralocorticoid Receptor Antagonists on Atrial Fibrillation Occurrence: A Systematic Review, Meta-Analysis, and Meta-Regression to Identify Modifying Factors.
Alexandre, J, Dolladille, C, Douesnel, L, Font, J, Dabrowski, R, Shavit, L, Legallois, D, Funck-Brentano, C, Champ-Rigot, L, Ollitrault, P, et al
Journal of the American Heart Association. 2019;(22):e013267
Abstract
Background Mineralocorticoid receptor antagonists (MRAs) have emerged as potential atrial fibrillation (AF) preventive therapy, but inconsistent results have been reported. We aimed to examine the effects of MRAs on AF occurrence and explore factors that could influence the magnitude of the effect size. Methods and Results PubMed, Embase, and Cochrane Central databases were used to search for randomized clinical trials and observational studies addressing the effect of MRAs on AF occurrence from database inception through April 03, 2018. We performed a systematic review and random effects meta-analyses to compute odds ratios with 95% CIs. Meta-regression was then applied to explore the sources of between-study heterogeneity. We included 24 studies, 11 randomized clinical trials and 13 observational cohorts, representing a total number of 7914 patients (median age: 64.2 years; median left ventricular ejection fraction: 49.7%; median follow-up: 12.0 months), 2843 (35.9%) of whom received MRA therapy. Meta-analyses showed a significant overall reduction in AF occurrence in the MRA-treated patients versus the control groups (15.0% versus 32.2%; odds ratio, 0.55; 95% CI, 0.44-0.70 [P<0.00001]), with the greatest benefit regarding recurrent AF episodes (odds ratio, 0.42; 95% CI, 0.31-0.59 [P<0.00001]) and with significant heterogeneity among the included studies (I2=54%; P=0.0008). Meta-regression analyses showed that effect size was significantly associated with older studies and higher AF occurrence rate in the control groups. Conclusions MRAs seem to be effective in AF prevention, especially regarding recurrent AF episodes.
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5.
Association Between Acute Fall in Estimated Glomerular Filtration Rate After Treatment for Primary Aldosteronism and Long-Term Decline in Renal Function.
Kobayashi, H, Abe, M, Nakamura, Y, Takahashi, K, Fujita, M, Takeda, Y, Yoneda, T, Kurihara, I, Itoh, H, Tsuiki, M, et al
Hypertension (Dallas, Tex. : 1979). 2019;(3):630-638
Abstract
Primary aldosteronism causes renal structural damage after glomerular hyperfiltration, and primary aldosteronism-specific treatment leads to an acute fall in estimated glomerular filtration rate (eGFR). We investigated whether this change affected the long-term eGFR slope in a retrospective cohort from the multicenter Japan Primary Aldosteronism Study. We allocated patients with primary aldosteronism to the adrenalectomy (n=202) and MR (mineralocorticoid receptor) antagonist (n=303) groups based on their treatment history and analyzed the association between the initial eGFR fall and long-term eGFR slope. The increased age, low serum potassium levels, high eGFR, and high plasma aldosterone levels were independent predictors for a large initial eGFR fall in both groups. Our analysis of tertiles based on the initial eGFR fall revealed that in the MR antagonist group, patients with a small initial eGFR fall had a significantly steeper long-term eGFR slope than those with a large initial fall (tertile 1 versus 2, P=0.025; tertile 1 versus 3, P=0.017). These associations were not identified in the adrenalectomy group. Thus, the smaller the acute fall in eGFR by initiation of MR antagonists, the greater was the rate of long-term eGFR decline. While the acute fall in eGFR induced by primary aldosteronism-specific treatment is occasionally a clinical concern, our findings highlight the favorable implications of the acute fall with respect to long-term renal outcomes.
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6.
Spironolactone and perioperative atrial fibrillation occurrence in cardiac surgery patients: Rationale and design of the ALDOCURE trial.
Alexandre, J, Ollitrault, P, Fischer, MO, Fellahi, JL, Rozec, B, Cholley, B, Dolladille, C, Chequel, M, Allouche, S, Legallois, D, et al
American heart journal. 2019;:88-96
Abstract
BACKGROUND After artery bypass grafting (CABG), the presence of perioperative AF (POAF) is associated with greater short- and long-term cardiovascular morbidity. Underlying POAF mechanisms are complex and include the presence of an arrhythmogenic substrate, cardiac fibrosis and electrical remodeling. Aldosterone is a key component in this process. We hypothesize that perioperative mineralocorticoid receptor (MR) blockade may decrease the POAF incidence in patients with a left ventricular ejection fraction (LVEF) ≥50% who are referred for CABG with or without aortic valve replacement (AVR). STUDY DESIGN The ALDOCURE trial (NCT03551548) will be a multicenter, randomized, double-blind, placebo-controlled trial testing the superiority of a low-cost MR antagonist (MRA, spironolactone) on POAF in 1500 adults referred for on-pump elective CABG surgery with or without AVR, without any history of heart failure or atrial arrhythmia. The primary efficacy end point is the occurrence of POAF from randomization to within 5 days after surgery, assessed in a standardized manner. The main secondary efficacy end points include the following: postoperative AF occurring within 5 days after cardiac surgery, perioperative myocardial injury, major cardiovascular events and death occurring within 30 days of surgery, hospital and intensive care unit length of stay, need for readmission, LVEF at discharge and significant ventricular arrhythmias within 5 days after surgery. Safety end points, including blood pressure, serum potassium levels and renal function, will be monitored regularly throughout the trial duration. CONCLUSION The ALDOCURE trial will assess the effectiveness of spironolactone in addition to standard therapy for reducing POAF in patients undergoing CABG. CLINICAL TRIAL REGISTRATION NCT03551548.
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7.
Mineralocorticoid antagonism enhances brown adipose tissue function in humans: A randomized placebo-controlled cross-over study.
Thuzar, M, Law, WP, Dimeski, G, Stowasser, M, Ho, KKY
Diabetes, obesity & metabolism. 2019;(3):509-516
Abstract
AIM: To investigate whether mineralocorticoid (MC) antagonism enhances brown adipose tissue (BAT) function in humans. MATERIALS AND METHODS In a randomized double-blind, cross-over designed trial, 10 healthy adults (two men, eight women) underwent 2 weeks of spironolactone (100 mg/d) treatment and placebo, with an intervening 2-week wash-out period. BAT function was assessed in response to cooling and to a mixed meal. Metabolic activity was measured by fluoro-deoxyglucose (FDG) uptake (maximal standardized uptake value, SUVmax ) using PET-CT. Thermogenic activity was measured by skin temperatures overlying supraclavicular (SCL) BAT depots using infrared thermography. Postprandial metabolism was measured by energy production rate (EPR) and lipid synthesis using indirect calorimetry. RESULTS During cooling, BAT metabolic activity (SUV 6.30 ± 2.16 vs 3.98 ± 1.34; P < 0.05) and volume (54.9 ± 22.8 vs 21.6 ± 11.8 cm3 ; P < 0.05) were significantly higher, and mean SCL temperature decreased by a smaller degree (-0.3°C°± 0.2°C vs -0.9°C ± 0.2°C; P = 0.05) with spironolactone treatment. A mixed meal increased SCL temperature and EPR. The postprandial rise in SCL temperature (+0.4°C ± 0.1°C vs +0.1°C ± 0.1°C; P < 0.05) but not in EPR was greater during spironolactone treatment. Postprandial lipid synthesis occurred in three participants with placebo but in none with spironolactone treatment (P = 0.06). CONCLUSION MC antagonism enhanced human BAT function in response to cooling and to a meal during which lipid synthesis was suppressed. As postprandial EPR comprises energy dissipated as heat and energy required to store nutrients, the reduction in lipid synthesis during MC antagonism is a probable consequence of concurrent stimulation of BAT thermogenesis. The shift in energy usage from storage to heat dissipation indicates that MC antagonists may have therapeutic benefit for obesity.
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8.
Optimally managing hyperkalemia in patients with cardiorenal syndrome.
Wang, AY
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(Suppl 3):iii36-iii44
Abstract
Renin-angiotensin-aldosterone system inhibitors (RAASi) are now a standard treatment in most patients with cardiovascular disease, especially in those with heart failure (HF). The European Society of Cardiology and the American College of Cardiology/American Heart Association gave a Class IA recommendation for the use of RAASi in the treatment of Classes II-IV symptomatic HF with reduced ejection fraction (HFREF), based on their strong clinical benefits of lowering all-cause mortality and HF hospitalizations in these subjects. However, RAASi therapy or adding mineralocorticoid receptor antagonists in subjects receiving background angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be associated with an increased risk of hyperkalemia (HK), especially in those with reduced kidney function. As a result, a significant proportion of these subjects either have RAASi dose reduced or more often discontinued when they develop HK. Discontinuation of RAASi in patients hospitalized with HFREF was associated with higher postdischarge mortality and rehospitalization rates, while optimal dosing of RAASi significantly reduced median hospital stays, outpatient visits and related costs. Thus, effective treatment is required to lower potassium level and maintain normokalemia in subjects with HF and reduced kidney disease who develop or are at risk of HK, thus enabling them to continue their RAASi therapy and maximize benefits from RAASi. In this review, we provide an up-to-date review of the prevalence and significance of HK in patients with cardiorenal syndrome, as well as their optimal management of HK with recent novel therapies.
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9.
Clinical and biochemical outcomes after adrenalectomy and medical treatment in patients with unilateral primary aldosteronism.
Katabami, T, Fukuda, H, Tsukiyama, H, Tanaka, Y, Takeda, Y, Kurihara, I, Ito, H, Tsuiki, M, Ichijo, T, Wada, N, et al
Journal of hypertension. 2019;(7):1513-1520
Abstract
OBJECTIVES Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling. METHODS Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia). RESULTS At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment. CONCLUSION Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.
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10.
Canrenone on cardiovascular mortality in congestive heart failure: CanrenOne eFFects on cardiovascular mortality in patiEnts with congEstIve hearT failure: The COFFEE-IT study.
Derosa, G, Maffioli, P, Scelsi, L, Bestetti, A, Vanasia, M, Cicero, AFG, Spinardi, L, Bentivenga, C, Esposti, DD, Caprio, M, et al
Pharmacological research. 2019;:46-52
Abstract
AIM: To evaluate canrenone effects compared to other therapies on cardiovascular mortality in patients with chronic heart failure (CHF) and preserved systolic function after 10 years of evaluation. METHODS We enrolled 532 patients with CHF and preserved systolic function. Patients were followed with a mean follow-up of 10 years: 166 patients were in therapy with canrenone, while 336 patients were in conventional therapy. We re-evaluated these data after 10 years, together with the rate of death and survival. RESULTS Systolic and diastolic blood pressure were lower with canrenone compared to the group not treated with canrenone, both in supine and orthostatism. In the group treated with canrenone we recorded a lower value of fasting plasma glucose and glycated hemoglobin. Uric acid was lower in the group treated with canrenone, no differences were observed regarding creatinine, sodium, potassium, brain natriuretic peptide (BNP), pro-BNP or plasma renin activity (PRA), while aldosterone levels were reduced in canrenone group compared to control. After 10 years, left ventricular mass was lower in canrenone group. We recorded a more pronounced progression of NYHA class in controls compared to patients treated with canrenone, with also a higher number of deaths. A higher number of deaths was recorded in control group in the 68-83 years range compared to canrenone. A higher incidence of death was reported among patients without hypercholesterolemia in control group; this was not significant in patients treated with canrenone. A longer survival was observed in patients treated with canrenone. CONCLUSION Administered to patients with CHF and preserved systolic fraction, reduced mortality and extended the life.