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Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure.

ABSTRACT: AIMS:Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF. METHODS AND RESULTS:We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all-cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT-CHF study, median renin and aldosterone levels were 85.3 (percentile25-75 = 28-247) ?IU/mL and 9.4 (percentile25-75 = 4.4-19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted-HR (95% CI) = 1.47 (1.16-1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted-HR (95% CI) = 1.16 (0.93-1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT-CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies. CONCLUSIONS:Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility.

SUBMITTER: Kobayashi M

PROVIDER: S-EPMC7261568 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure.

Kobayashi Masatake M Stienen Susan S Ter Maaten Jozine M JM Dickstein Kenneth K Samani Nilesh J NJ Lang Chim C CC Ng Leong L LL Anker Stefan D SD Metra Macro M Preud'homme Gregoire G Duarte Kevin K Lamiral Zohra Z Girerd Nicolas N Rossignol Patrick P van Veldhuisen Dirk J DJ Voors Adriaan A AA Zannad Faiez F Ferreira João Pedro JP

ESC heart failure 20200313 3

<h4>Aims</h4>Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF.<h4>Methods and results</h4>We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored ...[more]

PMID: 32167681

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Project description:Rationale & objectiveHeart failure treatment relies on loop diuretics to induce natriuresis and decongestion, but the therapy is often limited by diuretic resistance. We explored the association of renin-angiotensin-aldosterone system (RAAS) activation with diuretic response.Study designObservational cohort.Setting & populationEuvolemic ambulatory adults with chronic heart failure were administered torsemide in a monitored environment.PredictorsPlasma total renin, active renin, angiotensinogen, and aldosterone levels. Urine total renin and angiotensinogen levels.OutcomesSodium output per doubling of diuretic dose and fractional excretion of sodium per doubling of diuretic dose.Analytical approachRobust linear regression models estimated the associations of each RAAS intermediate with outcomes.ResultsThe analysis included 56 participants, and the median age was 65 years; 50% were women, and 41% were Black. The median home diuretic dose was 80-mg furosemide equivalents. In unadjusted and multivariable-adjusted models, higher levels of RAAS measures were generally associated with lower diuretic efficiency. Higher plasma total renin remained significantly associated with lower sodium output per doubling of diuretic dose (β = -0.41 [-0.76, -0.059] per SD change) with adjustment; higher plasma total and active renin were significantly associated with lower fractional excretion of sodium per doubling of diuretic dose (β = -0.48 [-0.83, -0.14] and β = -0.51 [-0.95, -0.08], respectively) in adjusted models. Stratification by RAAS inhibitor use did not substantially alter these associations.LimitationsSmall sample size; highly selected participants; associations may not be causal.ConclusionsAmong multiple measures of RAAS activation, higher plasma total and active renin levels were consistently associated with lower diuretic response. These findings highlight the potential drivers of diuretic resistance and underscore the need for high-quality trials of decongestive therapy enhanced by RAAS blockade.

Project description:The purpose of this study was to assess the relationship between biomarkers of renin-angiotensin-aldosterone system (RAAS) activation and decongestion strategies, worsening renal function, and clinical outcomes.High-dose diuretic therapy in patients with acute heart failure (AHF) is thought to activate the RAAS; and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation.This study analyzed 427 AHF patients enrolled in the DOSE-AHF (Diuretic Optimization Strategies in Acute Heart Failure) and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trials. We assessed the relationship between 2 markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72 h and 96 h and decongestion strategy: high- versus low-dose and continuous infusion versus bolus furosemide for DOSE-AHF and UF versus stepped pharmacologic care for CARRESS-HF. We determined the relationships between RAAS biomarkers and 60-day outcomes.Patients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium levels, and higher blood urea nitrogen (BUN) concentration. Continuous infusion furosemide and UF were associated with greater PRA increases (median: +1.66 vs. +0.66 ng/ml/h with continuous vs. bolus infusion, respectively, p = 0.021; +4.05 vs. +0.56 ng/ml/h with UF vs. stepped care, respectively, p = 0.014). There were no significant differences in RAAS biomarker changes with high- versus low-dose diuretic therapy (both: p > 0.5). Neither baseline log PRA nor log aldosterone was associated with increased death or HF hospitalization (hazard ratio [HR] for a doubling of 1.05; 95% confidence interval [CI]: 0.98 to 1.13; p = 0.18; and HR: 1.13; 95% CI: 0.99 to 1.28; p = 0.069, respectively). The change in RAAS biomarkers from baseline to 72 and 96 h was not associated with outcomes (both: p > 0.5).High-dose loop diuretic therapy did not result in RAAS activation greater than that with low-dose diuretic therapy. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. (Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure [DOSE-AHF]; NCT00577135; Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome [CARRESS]; NCT00608491).

Project description:AimsDespite of recent advances in the pharmacological treatment, heart failure (HF) maintains significant morbidity and mortality rates. While serum potassium disorders are common and associated with adverse outcomes, the exact recommended potassium level for patients with HF are not entirely established. We aimed to investigate the prognostic role of potassium levels on a cohort of patients with symptomatic chronic HF.Methods and resultsPatients with symptomatic chronic HF were identified at the referral to 6 min walking test (6MWT) and were prospectively followed up for cardiovascular events. Clinical and laboratorial data were retrospectively obtained. The primary endpoint was the composite of cardiovascular death, hospitalization due to HF, and heart transplantation. The cohort included 178 patients with HF with the mean age of 51 ± 12.76 years, 39% were female, 85% of non-ischaemic cardiomyopathy, and 38% had New York Heart Association Class III with a relatively high Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score (12.91 ± 6.6). The mean left ventricular ejection fraction was 39.98 ± 15.79%, and the mean 6MWT distance was 353 ± 136 m. After a median follow-up of 516 days, there were 22 major cardiovascular events (4 cardiovascular deaths, 13 HF admissions, and 5 heart transplants). Patients were stratified according to cut-point level of serum potassium of 4.7 mmol/L to predict combined cardiac events based on receiver operating characteristic analysis. Individuals with higher potassium levels had worse renal function (glomerular filtration rate, K ≤ 4.7: 102.8 ± 32.2 mL/min/1.73 m2 vs. K > 4.7: 85.42 ± 36.2 mL/min/1.73 m2 , P = 0.004), higher proportion of New York Heart Association Class III patients (K ≤ 4.7: 28% vs. K > 4.7: 48%, P = 0.0029), and also higher MAGGIC score (K ≤ 4.7: 12.08 ± 5.7 vs. K > 4.7: 14.9 ± 7.9, P = 0.0089), without significant differences on the baseline pharmacological HF treatment. Both potassium levels [hazard ratio (HR) 4.26, 95% confidence interval (CI) 1.59-11.421, P = 0.003] and 6MWT distance (HR 0.99, 95% CI 0.993-0.999, P = 0.01) were independently associated with the primary outcome. After adjustments for MAGGIC score and 6MWT distance, potassium levels > 4.7 mmol/L maintained a significant association with outcomes (HR 3.57, 95% CI 1.305-9.807, P = 0.013). Patients with K > 4.7 mmol/L were more likely to present clinical events during the follow-up (log rank = 0.005). Adding potassium levels to the model including 6MWT and MAGGIC significantly improved the prediction of events over 2 years (integrated discrimination index 0.105, 95% CI 0.018-0.281, P = 0.012 and net reclassification index 0.447, 95% CI 0.077-0.703, P = 0.028).ConclusionsPotassium levels were independently associated with worse outcomes in patients with chronic symptomatic HF, also improving the accuracy model for prognostic prediction when added to MAGGIC score and 6MWT distance. The potassium levels above 4.7 mmol/L might identify those patients at an increased risk of cardiovascular events.

Project description:Objective1,25-Dihydroxyvitamin D (1,25([OH]2D) is considered to be a negative endogenous regulator of the renin-angiotensin-aldosterone system (RAAS), but the effect of vitamin D supplementation on the RAAS is inconclusive.DesignIn this prespecified secondary analysis of a randomized controlled trial, we assessed in 165 patients with heart failure (vitamin D group: n = 83; placebo group: n = 82) the effect of three years of vitamin D supplementation with 4000 IU daily on parameters of the RAAS (renin and aldosterone) and on circulating 1,25(OH)2D, plasma phosphate, and fibroblast growth factor (FGF)-23. We assessed age- and baseline-adjusted between-group differences at study termination.ResultsAlmost all patients were under treatment with beta-blockers, inhibitors of the RAAS, and diuretics. Initially, the frequency of concentrations above the laboratory-specific reference range (renin: >23.9 mIU/L; aldosterone: >232 ng/L) in the vitamin D and placebo group was 87.7% and 92.7%, respectively (renin), and 24.1% and 32.5%, respectively (aldosterone). Vitamin D increased adjusted 1,25(OH)2D concentrations significantly (mean treatment effect and 95% CI: 18.3 pmol/L,7.3 to 29.3 pmol/L; P < 0.001) but had no significant effects on phosphate (0.18 mmol/L, -0.00 to 0.35 mmol/L; P = 0.051), FGF-23 (685 RU/mL, -213 to 1585 RU/mL; P = 0.134), renin (312 mIU/L, -279 to 902 ng/L; P = 0.298), or aldosterone (-0.19 ng/L, -5.09 to 4.70 ng/L; P = 0.938). Vitamin D supplementation was, however, associated with an increase in renin concentrations in the subgroup with baseline 25-hydroxyvitamin D below 30 nmol/L (n = 67; 1365 mIU/, 343 to 2386 mIU/L; P = 0.010).ConclusionsIn patients with advanced heart failure treated according to evidence-based guidelines, vitamin D supplementation did not significantly influence parameters of the RAAS in the entire study cohort but was associated with an increase in plasma renin concentrations in the subgroup with low baseline 25-hydroxyvitamin D concentrations.

Project description:AimsRecently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1-7) [Ang (1-7)]. Ang (1-7) is part of the angiotensin-converting enzyme-Ang (1-7)-Mas pathway which is considered to antagonize the renin-angiotensin-aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.Methods and resultsDipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3-LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin [78.3 (interquartile range, IQR 26.3-227.7) vs. 120.7 IU/mL (IQR 34.74-338.9), P < 0.001, for Q1-3 vs. Q4] and aldosterone [88 (IQR 44-179) vs. 116 IU/mL (IQR 46-241), P < 0.001, for Q1-3 vs. Q4] concentrations. The strongest independent predictors for higher concentration of DPP3 were log-alanine aminotransferase, log-total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor-23 and N-terminal pro-B-type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant.ConclusionsIn patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.

Project description:AIMS:This study aimed to evaluate the prognostic significance of nutritional status in post-discharge Asians with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS:We examined the prognostic implications of body mass index (BMI) and nutritional markers among consecutive patients hospitalized for HFpEF. Nutritional metrics were estimated by serum albumin (SA), prognostic nutritional index (PNI), Controlling Nutritional Status (CONUT) score, and geriatric nutritional risk index. Among 1120 patients (mean age: 77.2 ± 12.6 years, 39.4% men), mean SA levels, PNI, CONUT scores, and geriatric nutritional risk index were 3.3 ± 0.6 g/dL, 40.2 ± 8.7, 5.5 ± 2.1, and 95.9 ± 14.5, respectively. Lean body size, higher white blood cell counts and C-reactive protein levels, anaemia, and lack of angiotensin blocker use were independently associated with malnutrition (defined by SA < 3.5 g/dL). Higher SA levels [hazard ratio (HR): 0.67 (95% confidence interval, CI: 0.53-0.85)], higher PNI [HR: 0.97 (95% CI: 0.95-0.99)], and higher geriatric nutritional risk index [HR: 0.98 (95% CI: 0.97-0.99)] (all P < 0.05) were all associated with longer survival, with higher CONUT score [HR: 1.08 (95% CI: 1.02-1.13)] exhibited higher mortality in Cox regression models and with higher SA levels/PNI but not BMI further contributing to the reduced rate of re-hospitalization (both P < 0.05). Categorizing BMI (25 kg/m2 as cut-off) and nutritional status showed significantly higher mortality rates among patients with lower BMI/malnutrition than among those with BMI/better nutrition (SA level, PNI, and CONUT score, all P < 0.01). Restricted cubic spline regression revealed a marked survival benefit of better nutrition with increasing BMI (adjusted Pinteraction for both SA level and PNI: <0.001; adjusted Pinteraction for CONUT score: 0.046). CONCLUSIONS:Malnutrition was frequently and strongly associated with systemic inflammation in Asian patients hospitalized for acute HFpEF. Our findings also indicate that nutrition may play a pivotal role in metabolic protection in this population.

Dataset Information

Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure.

Publications

Clinical determinants and prognostic implications of renin and aldosterone in patients with symptomatic heart failure.

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