scholarly journals Aldosterone and Mineralocorticoid Receptor Signaling as Determinants of Cardiovascular and Renal Injury: From Hans Selye to the Present

2021 ◽  
pp. 1-8
Author(s):  
Murray Epstein
Keyword(s):  
Heart Failure ◽  
Kidney Failure ◽  
Lower Risk ◽  
Mineralocorticoid Receptor ◽  
Therapeutic Potential ◽  
Mechanisms Of Action ◽  
Secondary Outcome ◽  
Future Studies ◽  
Collagen Formation ◽  
Outcome Event

<b><i>Background:</i></b> A full understanding of the mechanisms of action of aldosterone and its interaction with the mineralocorticoid receptor (MR) allows a theoretical framework to predict the therapeutic potential of MR antagonists (MRAs) in CKD, and heart failure with reduced ejection fraction. <b><i>Summary:</i></b> The initial focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function. In contrast, many recent studies have demonstrated a wider and expanded role for aldosterone in modulating inflammation, collagen formation, fibrosis, and necrosis. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of CKD. By promoting inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and its associated morbidity and mortality. In accord with this mechanism of action, blockade of the MR is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes who were treated with finerenone (a novel nonsteroidal MRA) manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure, or a sustained decrease of ≥40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). <b><i>Key Messages:</i></b> Based on the success of the FIDELIO-DKD study, future studies should be implemented testing the hypothesis that a wide array of nondiabetic CKD is modulated by overactivation of the MR, and consequently may be amenable to treatment with novel nonsteroidal MRAs. Future studies are encouraged to elucidate the clinical implications of the interplay of nonsteroidal MRAs and the components of the renin-angiotensin cascade. The unique and recently reported interrelationship of fibroblast growth factor (FGF23) and aldosterone may also constitute a propitious subject for future investigation.

Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events After Acute Kidney Injury

2022 ◽  
pp. ASN.2021060757
Author(s):  
Sherry Mansour ◽  
Pavan Bhatraju ◽  
Steven Coca ◽  
Wassim Obeid ◽  
Francis Wilson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Lower Risk ◽  
Kidney Injury ◽  
Early Response ◽  
Secondary Outcome ◽  
Ckd Progression ◽  
Angiopoietin 2 ◽  
Vessel Stability

Background The mechanisms underlying long-term sequelae following acute kidney injury (AKI) remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for chronic kidney disease (CKD) and heart failure. Methods To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure, as well as the secondary outcome of all-cause mortality 3 months after discharge or later. Results Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [95% CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression. Conclusions A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.

1136Prognostic impact of mineralocorticoid receptor antagonists in patients hospitalized for acute heart failure

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Yaku ◽  
T Kato ◽  
T Morimoto ◽  
Y Inuzuka ◽  
Y Tamaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Lower Risk ◽  
Mineralocorticoid Receptor ◽  
Primary Outcome ◽  
Outcome Measure ◽  
Primary Outcome Measure ◽  
Matched Cohort ◽  
Mineralocorticoid Receptor Antagonists ◽  
Receptor Antagonists

Abstract Background The favourable effect of mineralocorticoid receptor antagonists (MRAs) on mortality was established in patients with stable heart failure (HF) with reduced ejection fraction (EF). However, its prognostic effect of MRAs in acute decompensated heart failure (ADHF) including HF with preserved EF (HFpEF) was unclear. Purpose This study sought to investigate the long-term impact of MRA on the post-discharge outcomes in patients with ADHF. Methods From the consecutive 3717 patients hospitalized for ADHF and discharged alive in the KCHF registry, we developed the propensity score (PS) for MRA use and constructed the PS-matched cohort. We compared the effect of MRA use on the primary outcome measure of all-cause death or HF hospitalization. Results A total of 1678 patients (45%) received MRA at discharge from the index hospitalization. Median follow-up was 470 days with 96% 1-year follow-up rate. In the PS-matched cohort (N=1034 in each group), the cumulative 1-year incidence of the primary outcome measure was significantly lower in the MRA group than in the no MRA group (28.4% vs. 33.9%, P=0.003) (Figure 1). The cumulative 1-year incidence of HF hospitalization was significantly lower in the MRA group than in the no MRA group (18.7% vs. 24.8%, P<0.001), while there was no difference in mortality between the 2 groups (15.6% vs. 15.8%, P=0.85). There was no interaction between the effect of MRA and the 3 subgroups stratified by EF (EF <40%, EF 40–49%, EF ≥50%) (interaction P=0.12). Figure 1 Conclusion The use of MRA was associated with lower risk for the primary composite outcome of all-cause death or HF hospitalization in patients hospitalized for ADHF including HFpEF, which was mainly driven by the lower risk for HF hospitalization.

scholarly journals Prognostic value of reduction in left atrial size during a follow-up of heart failure: an observational study

BMJ Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. e044409
Author(s):  
Masayuki Shiba ◽  
Takao Kato ◽  
Takeshi Morimoto ◽  
Hidenori Yaku ◽  
Yasutaka Inuzuka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Lower Risk ◽  
Left Atrial ◽  
Primary Outcome ◽  
Outcome Measure ◽  
No Reduction ◽  
Primary Outcome Measure ◽  
Secondary Outcome ◽  
Group Change

ObjectiveThe association between sequential changes in left atrial diameter (LAD) and prognosis in heart failure (HF) remains to be elucidated. The present study aimed to investigate the link between reduction in LAD and clinical outcomes in patients with HF.DesignA multicentre prospective cohort study.SettingThis study was nested from the Kyoto Congestive Heart Failure registry including consecutive patients admitted for acute decompensated heart failure (ADHF) in 19 hospitals throughout Japan.ParticipantsThe current study population included 673 patients with HF who underwent both baseline and 6-month follow-up echocardiography with available paired LAD data. We divided them into two groups: the reduction in the LAD group (change <0 mm) (n=398) and the no-reduction in the LAD group (change ≥0 mm) (n=275).Primary and secondary outcomesThe primary outcome measure was a composite of all-cause death or hospitalisation for HF during 180 days after 6-month follow-up echocardiography. The secondary outcome measures were defined as the individual components of the primary composite outcome measure and a composite of cardiovascular death or hospitalisation for HF.ResultsThe cumulative 180-day incidence of the primary outcome measure was significantly lower in the reduction in the LAD group than in the no-reduction in the LAD group (13.3% vs 22.2%, p=0.002). Even after adjusting 15 confounders, the lower risk of reduction in LAD relative to no-reduction in LAD for the primary outcome measure remained significant (HR 0.59, 95% CI 0.36 to 0.97 p=0.04).ConclusionPatients with reduction in LAD during follow-up after ADHF hospitalisation had a lower risk for a composite endpoint of all-cause death or HF hospitalisation, suggesting that the change of LAD might be a simple and useful echocardiographic marker during follow-up.

The Role of Mineralocorticoid Receptor Antagonists in the Management of Heart Failure with Preserved Ejection Fraction

2019 ◽  
Vol 24 (46) ◽  
pp. 5525-5527 ◽  
Author(s):  
Achilleas Papagiannis ◽  
Stelina Alkagiet ◽  
Konstantinos Tziomalos
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mineralocorticoid Receptor ◽  
Therapeutic Potential ◽  
Preserved Ejection Fraction ◽  
Mineralocorticoid Receptor Antagonists ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Definition Of

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with increased risk for hospitalization and all-cause mortality. Currently, there is no established treatment to improve the survival of these patients. Aldosterone appears to play a role in the pathogenesis of HFpEF. Objective: To discuss the findings of studies that evaluated the effects of mineralocorticoid receptor (MR) antagonists on the outcome of patients with HFpEF. Methods: PubMed was searched for relevant papers. References of retrieved articles were also evaluated for pertinent material. Results: Accumulating data suggest that MR antagonists might be useful in the management of patients with HFpEF. However, existing evidence is limited and conflicting. Conclusions: More studies are needed to clearly define the therapeutic potential of MR antagonists in HFpEF. Given the heterogeneity of this disease and the low specificity of the criteria used for its diagnosis, it is also important to improve the definition of HFpEF and include appropriately selected patients in these studies.

P0771STOPPING MINERALOCORTICOID RECEPTOR ANTAGONISTS AFTER HYPERKALEMIA AND RISK OF ADVERSE OUTCOMES IN PATIENTS WITH HEART FAILURE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Marco Trevisan ◽  
Yang Xu ◽  
Yao Qiao ◽  
Gianluigi Savarese ◽  
Lars Lund ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mineralocorticoid Receptor ◽  
Cox Regression ◽  
Secondary Outcome ◽  
Composite Outcome ◽  
Mineralocorticoid Receptor Antagonists ◽  
Receptor Antagonists ◽  
Heart Failure Patients ◽  
Patients With Heart Failure ◽  
Primary Composite Outcome

Abstract Background and Aims Stopping mineralocorticoid receptor antagonists (MRAs) after an episode of hyperkalemia is common, particularly among patients with chronic kidney disease (CKD). This may involve therapeutic compromises, in that the cessation of MRAs deprives patients of their beneficial cardiovascular effects. The aim of this study is to determine the risks of adverse health outcomes in heart failure patients after an episode of hyperkalemia, comparing users of MRA who stop treatment to those who continue the drugs. Method Observational study from the Stockholm Creatinine Measurements (SCREAM) project. We identified patients with heart failure patients initiating MRAs and surviving a first-detected episode of hyperkalemia (plasma potassium &gt;5.0 mmol/L). We used Cox regression, adjusting for multiple confounders, to estimate hazard ratios (HR) for adverse events following hyperkalemia. The primary outcome was the composite of hospital admission with heart failure, stroke, myocardial infarction or death. The secondary outcome was a new hyperkalemia event. We compared risks between people who stopped MRA treatment and those who continued MRA within 4 months from the hyperkalemia event (landmark analysis at month 4 after event). Results We identified 1,330 patients with heart failure that developed hyperkalemia after initiating MRA therapy. Their median age was 80 years, 46% were women and their median eGFR was 43 ml/min/1.73m2. Of those, 595 (45%) had discontinued MRA by 4 months after hyperkalemia. Patients who stopped MRA were more likely to have eGFR &lt;60 ml/min/1.73m2 (81% vs 71%), had a more severe index hyperkalemia (potassium&gt;5.5 mmol/L, 35% vs 21%), and had hyperkalemia occur earlier in the course of MRA therapy (within 3 months from MRA initiation, 66% vs 51%). During median 1.5 years of follow-up, a total of 846 patients (64%) experienced the primary composite outcome. Compared to patients who discontinued MRA, those who continued had a similar risk of the primary composite outcome (HR 0.95, 95% CI 0.82-1.10). A total of 569 patients (43%) developed a subsequent hyperkalemia event. Compared to patients who discontinued MRA, those who continued with the therapy were at higher risk of another hyperkalemia (HR 1.46, 95% CI 1.21-1.75). Results were consistent across age strata, sex and presence of CKD. Conclusion Continuing treatment with MRA after an episode of hyperkalemia was not associated with different medium-term cardiovascular risk compared to those who stopped the drugs.

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