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Acta Neuropathologica Communications Jun 2024A link between chronic stress and Parkinson's disease (PD) pathogenesis is emerging. Ample evidence demonstrates that the presynaptic neuronal protein alpha-synuclein...
A link between chronic stress and Parkinson's disease (PD) pathogenesis is emerging. Ample evidence demonstrates that the presynaptic neuronal protein alpha-synuclein (asyn) is closely tied to PD pathogenesis. However, it is not known whether stress system dysfunction is present in PD, if asyn is involved, and if, together, they contribute to neurodegeneration. To address these questions, we assess stress axis function in transgenic rats overexpressing full-length wildtype human asyn (asyn BAC rats) and perform multi-level stress and PD phenotyping following chronic corticosterone administration. Stress signaling, namely corticotropin-releasing factor, glucocorticoid and mineralocorticoid receptor gene expression, is also examined in post-mortem PD patient brains. Overexpression of human wildtype asyn leads to HPA axis dysregulation in rats, while chronic corticosterone administration significantly aggravates nigrostriatal degeneration, serine129 phosphorylated asyn (pS129) expression and neuroinflammation, leading to phenoconversion from a prodromal to an overt motor PD phenotype. Interestingly, chronic corticosterone in asyn BAC rats induces a robust, twofold increase in pS129 expression in the hypothalamus, the master regulator of the stress response, while the hippocampus, both a regulator and a target of the stress response, also demonstrates elevated pS129 asyn levels and altered markers of stress signalling. Finally, defective hippocampal stress signalling is mirrored in human PD brains and correlates with asyn expression levels. Taken together, our results link brain stress system dysregulation with asyn and provide evidence that elevated circulating glucocorticoids can contribute to asyn-induced neurodegeneration, ultimately triggering phenoconversion from prodromal to overt PD.
Topics: alpha-Synuclein; Animals; Parkinson Disease; Humans; Rats, Transgenic; Rats; Stress, Psychological; Male; Corticosterone; Brain; Hypothalamo-Hypophyseal System; Female; Pituitary-Adrenal System
PubMed: 38886854
DOI: 10.1186/s40478-024-01797-w -
JCI Insight Jun 2024Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among them recessive mutations in the steroidogenic enzymes...
Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among them recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase (FDXR) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-Related Mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, FRM patients often experience worsening or demise following stress associated with infections. We investigated two female FRM patients carrying the novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic FDXR-variant cell lines reprogrammed from three FRM patients' fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally, Fdxr-mutant mice allelic to the severe p.R386W human variant, showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human FDXR variants may cause compensated, but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.
PubMed: 38885337
DOI: 10.1172/jci.insight.179071 -
The American Journal of the Medical... Jun 2024Incomplete decongestion is the main cause of readmission in the early post-discharge period of a hospitalization for acute heart failure. Recent heart failure guidelines... (Review)
Review
Incomplete decongestion is the main cause of readmission in the early post-discharge period of a hospitalization for acute heart failure. Recent heart failure guidelines have highlighted initiation and rapid up-titration of quadruple therapy with angiotensin receptor neprilysin inhibitor, beta adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor to prevent hospitalizations for heart failure with reduced ejection fraction. However, full decongestion remains the foremost therapeutic goal of hospitalization for heart failure. While early addition of sodium glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists may be helpful, the value of the other therapeutics comes after decongestion is complete.
PubMed: 38880301
DOI: 10.1016/j.amjms.2024.06.002 -
The Annals of Thoracic Surgery Jun 2024There is an evolving role for guideline directed medical therapy (GDMT) in managing heart failure with reduced ejection fraction (HFrEF) following cardiac surgery. GDMT... (Review)
Review
There is an evolving role for guideline directed medical therapy (GDMT) in managing heart failure with reduced ejection fraction (HFrEF) following cardiac surgery. GDMT is based on the use of pharmacological agents from each of the four distinct drug classes, also known as the four pillars of heart failure therapy; beta blockers, renin-angiotensin system inhibitors often paired with neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. Despite the demonstrated benefits of GDMT in reducing mortality and hospitalization rates in the non-surgical literature, there is conspicuous underutilization of GDMT following cardiac surgery. The lack of published literature and practical challenges surrounding the timing for initiation of GDMT in the immediate postoperative period have limited standardized implementation strategies. A multidisciplinary approach will be necessary to assist in initiating, titrating, and monitoring the response to these therapies in HFrEF patients following cardiac surgery.
PubMed: 38878947
DOI: 10.1016/j.athoracsur.2024.05.034 -
JACC. Heart Failure May 2024Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused...
BACKGROUND
Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns.
OBJECTIVES
The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk).
METHODS
REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6]).
RESULTS
Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m, 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily.
CONCLUSIONS
REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone; NCT04676646).
PubMed: 38878009
DOI: 10.1016/j.jchf.2024.05.003 -
Journal of Pharmacy Practice Jun 2024Chronic kidney disease (CKD) affects approximately 14% of adults in the United States and is present in at least 10% of the population worldwide. Blood glucose and blood... (Review)
Review
Chronic kidney disease (CKD) affects approximately 14% of adults in the United States and is present in at least 10% of the population worldwide. Blood glucose and blood pressure control are imperative to adequately manage CKD as they are the only primary prevention measures for the condition. Recent changes in CKD evaluation and medication therapies that modify disease progression and aid in managing complications such as anemia of CKD have emerged, including a newly approved mineralocorticoid receptor antagonist and hypoxia-inducible factor-prolyl hydroxylase inhibitor, respectively. This focused update on CKD evaluation and management will review the most recent evidence and approved agents to support patients with CKD, including a review of glomerular filtration rate measurement methods such as CKD-EPI 2021 and utilization of cystatin C, Kidney Disease Improving Global Outcomes (KDIGO) guidelines, American Diabetes Association (ADA) guidelines, and primary literature supporting the use of newer agents in CKD. Checklists for managing blood pressure and blood glucose, CKD-mineral bone disorder, and anemia of CKD targeted for pharmacists are also provided. Additionally, a discussion of Centers for Medicare & Medicaid (CMS) coverage of agents approved for managing complications of CKD is included.
PubMed: 38877746
DOI: 10.1177/08971900241262381 -
Revue Medicale de Liege Jun 2024Preventing chronic kidney disease (CKD) is a major public health objective. CKD leads to significant cardiovascular morbidity and mortality, with a negative impact on... (Review)
Review
Preventing chronic kidney disease (CKD) is a major public health objective. CKD leads to significant cardiovascular morbidity and mortality, with a negative impact on quality of life and significant societal repercussions. Several drugs are effective in preventing and curbing CKD, including blockers of the renin/angiotensin/aldosterone system and inhibitors of the SGLT2 co-transporter. New molecules are currently in clinical trials focusing on the nephro-protection, such as non-steroidal mineralocorticoid receptor antagonists and GPL-1 receptor agonists. In addition to this drug arsenal, CKD prevention also relies on non-pharmacological optimization of hygienic-dietary measures, including smoking avoidance, physical activity and dietetics. The aim of this article is to detail this non-medicinal approach to the prevention and slow down of CKD.
Topics: Humans; Renal Insufficiency, Chronic
PubMed: 38869132
DOI: No ID Found -
Revue Medicale Suisse Jun 2024Primary aldosteronism is the most common cause of secondary hypertension in the middle-aged population. A high level of suspicion is required, due to the higher...
Primary aldosteronism is the most common cause of secondary hypertension in the middle-aged population. A high level of suspicion is required, due to the higher morbidity and mortality associated with damage to target organs (heart, brain, vessels, kidneys) than with essential hypertension. Screening involves 3 phases: detection, confirmation and detection of lateralization if surgery is an option. The choice of treatment will depend on the cause and the patient's wishes and may be either medical (mineralocorticoid receptor antagonists) or surgical (unilateral adrenalectomy). Both treatment options reduce the risk of cardiovascular morbidity and mortality if blood pressure is well controlled.
Topics: Humans; Hyperaldosteronism; Adrenalectomy; Hypertension; Mineralocorticoid Receptor Antagonists; Middle Aged
PubMed: 38867561
DOI: 10.53738/REVMED.2024.20.878.1163 -
The Journal of Steroid Biochemistry and... Jun 2024The mineralocorticoid receptor (MR, NR3C2) mediates ion and water homeostasis in epithelial cells of the distal nephron and other tissues. Aldosterone, the prototypical...
The mineralocorticoid receptor (MR, NR3C2) mediates ion and water homeostasis in epithelial cells of the distal nephron and other tissues. Aldosterone, the prototypical mineralocorticoid, regulates electrolyte and fluid balance. Cortisol binds to MR with equal affinity to aldosterone, but many MR-expressing tissues inactivate cortisol to cortisone via 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2). Dysregulated MR activation contributes to direct cardiovascular tissue insults. Besides aldosterone and cortisol, a variety of MR agonists and/or HSD11B2 inhibitors are putative players in the pathophysiology of low-renin hypertension (LRH), and cardiovascular and metabolic pathology. We developed an in vitro human MR (hMR) model, to facilitate screening for MR agonists, antagonists, and HSD11B2 inhibitors. The CV1 monkey kidney cells were transduced with lentivirus to stably express hMR and an MR-responsive gaussia luciferase gene. Clonal populations of MR-expressing cells (CV1-MRluc) were further transduced to express HSD11B2 (CV1-MRluc-HSD11B2). CV1-MRluc and CV1-MRluc-HSD11B2 cells were treated with aldosterone, cortisol, 11-deoxycorticosterone (DOC), 18-hydroxycorticosterone (18OHB), 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), progesterone, or 17-hydroxyprogesterone (17OHP). In CV1-MRLuc cells, aldosterone and DOC displayed similar potency (EC50: 0.45 nM and 0.30 nM) and maximal response (31- and 23-fold increase from baseline) on hMR; 18oxoF and 18OHB displayed lower potency (19.6 nM and 56.0 nM, respectively) but similar maximal hMR activation (25- and 27-fold increase, respectively); cortisol and corticosterone exhibited higher maximal responses (73- and 52-fold, respectively); 18OHF showed no MR activation. Progesterone and 17OHP inhibited aldosterone-mediated MR activation. In the MRluc-HSD11B2 model, the EC50 of cortisol for MR activation increased from 20 nM (CV1-MRLuc) to ∼2000 nM, while the EC50 for aldosterone remained unchanged. The addition of 18β-glycyrrhetinic acid (18β-GA), a HSD11B2 inhibitor, restored the potency of cortisol back to ∼70 nM in CV1-hMRLuc-HSD11B2 cells. Together, these two cell models will facilitate the discovery of novel MR-modulators, informing MR-mediated pathophysiology mechanisms and drug development efforts.
PubMed: 38866188
DOI: 10.1016/j.jsbmb.2024.106568 -
Cardiovascular Drugs and Therapy Jun 2024This study aims to compare the addition of SGLT2 inhibitors or doubling the diuretic dose in patients receiving treatment with beta-blockers, angiotensin-converting...
INTRODUCTION
This study aims to compare the addition of SGLT2 inhibitors or doubling the diuretic dose in patients receiving treatment with beta-blockers, angiotensin-converting enzyme inhibitors (ACEi), or angiotensin receptor blockers (ARB), as well as mineralocorticoid receptor antagonists (MRA), for heart failure with reduced ejection fraction (HFrEF) who present to the emergency department with decompensated heart failure.
METHODS
This study is a single-center and prospective analysis. A total of 980 decompensated heart failure (HFrEF) patients receiving optimal medical therapy (OMT) according to the 2021 European heart failure guidelines were randomized in a 2:1 ratio into the furosemide and empagliflozin treatment arms. The analysis includes patient clinical characteristics, laboratory results, and echocardiographic data. Factors influencing rehospitalization were identified through multivariate Cox regression analysis. Log-rank analysis was employed to assess factors affecting rehospitalization.
RESULTS
The mean age of the patients was 67.9 years, with 52.1% being men. There was no significant impact of demographic, clinical, or echocardiographic factors on rehospitalization at 1 month; only the effect of treatment subgroups on rehospitalization was observed (p = 0.039). Significant echocardiographic and clinical improvements were seen in both treatment arms. The empagliflozin group exhibited significant improvements in 6-min walk distance, heart rate, body weight, NT-pro BNP levels, and eGFR level compared to the furosemide group. The rate of rehospitalization in the first month was significantly lower in those receiving empagliflozin (28.7%) compared to those receiving a double dose of furosemide (40.2%) (log-rank p = 0.013).
DISCUSSION AND CONCLUSION
This study provides valuable insights into the management of decompensated HFrEF and demonstrates that SGLT2 inhibitors offer benefits beyond glycemic control in this patient group. The significant reduction in rehospitalization rates and improvements in echocardiographic parameters underscore the potential of SGLT2 inhibitors in reducing acute heart failure episodes.
PubMed: 38864970
DOI: 10.1007/s10557-024-07593-x