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Abstract: Glucocorticoid receptors are essential for normal development and stress responses. Their role in H 2 O and Na + metabolism, especially in chronic heart failure (CHF), is not well defined. In a previous study, we found that glucocorticoids potentiate urination in CHF and promote H 2 O excretion by inhibiting the vasopressin receptor 2 pathway. The present study examines the effect of glucocorticoids on renal Na + excretion and the underlying mechanisms in CHF rats with acute sodium loading. CHF was induced by left coronary artery ligation for 8 weeks. Rats were randomly assigned to 5 groups: control, CHF, dexamethasone (DEX)-administered CHF, DEX-administered CHF treated with RU486 (mifepristone, a glucocorticoid receptor antagonist), and RU486-treated CHF. An acute sodium loading test was performed 6 hours after DEX administration. Blood and urine samples were collected, and hemodynamics were measured. The expression and localization of Na + transporter proteins were determined by immunoblotting and immunohistochemistry. DEX increased the urine volume and urinary sodium and improved cardiac function and the estimated glomerular filtration rate in CHF rats. The upregulation of the epithelial sodium channel β and γ subunits, Na-K-2Cl cotransporter, serum glucocorticoid-regulated kinase 1 (SGK1), and Na + /K + -ATPase in the renal epithelium of CHF rats was downregulated by DEX. These beneficial effects were abolished by RU486. The expression of natriuretic peptide receptor A was opposite that of the above proteins. Glucocorticoids might induce profound natriuresis in CHF rats during acute sodium loading, which is associated with downregulating some Na + transporter proteins in the renal epithelium and improving intrarenal hemodynamics., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ivabradine has potent actions in reducing heart rate and improving clinical outcomes of chronic heart failure with reduced ejection fraction (HFrEF). At present, only the short-acting formulation of ivabradine is available that needs to be administered twice daily., Objectives: This study sought to evaluate the role of ivabradine hemisulfate sustained release (SR), a novel long-acting formulation of ivabradine dosed once daily, in stable patients with HFrEF., Methods: Patients with stabilized HFrEF in New York Heart Association functional class II-IV were enrolled and randomized to receive placebo or ivabradine SR in addition to standard medications. The primary endpoint was the change of left ventricular (LV) end-systolic volume index from baseline to week 32., Results: We randomly assigned 181 patients to placebo and 179 patients to ivabradine SR. After 32 weeks, a significant improvement of LV end-systolic volume index from baseline was observed in both arms with a greater effect in the ivabradine SR arm. Ivabradine SR therapy also exhibited superiority in improving LV end-diastolic volume index, LV ejection fraction, resting heart rate, the Kansas City Cardiomyopathy Questionnaire score, and hospital admission for heart failure worsening and cardiovascular disease in comparison to placebo. Overall adverse events showed no difference between the treatment arms. There were fewer occurrences of worsening heart failure in the ivabradine SR arm., Conclusions: The present study demonstrates that ivabradine SR once daily in addition to optimum standard therapy improved heart function in patients with HFrEF. (Clinical Trial of Systolic Heart Failure Treatment of IvabRadine Hemisulfate Sustained-release Tablets [FIRST]; NCT02188082)., Competing Interests: Funding Support and Author Disclosures This work was supported by Jiangsu Hengrui Pharmaceuticals, Lianyungang, China. Jiangsu Hengrui Pharmaceuticals provided the investigational medicinal products and an unrestricted grant. Drs Lou and Cui are full-time employees of Jiangsu Hengrui Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Arginine vasopressin dependent antidiuresis plays a key role in water-sodium retention in heart failure. In recent years, the role of glucocorticoids in the control of body fluid homeostasis has been extensively investigated. Glucocorticoid deficiency can activate V2R (vasopressin receptor 2), increase aquaporins expression, and result in hyponatremia, all of which can be reversed by glucocorticoid supplement. Methods and Results Heart failure was induced by coronary artery ligation for 8 weeks. A total of 32 rats were randomly assigned to 4 groups (n=8/group): sham surgery group, congestive heart failure group, dexamethasone group, and dexamethasone in combination with glucocorticoid receptor antagonist RU486 group. An acute water loading test was administered 6 hours after drug administration. Left ventricular function was measured by a pressure-volume catheter. Protein expressions were determined by immunohistochemistry and immunoblotting. The pressure-volume loop analysis showed that dexamethasone improves cardiac function in rats with heart failure. Western blotting confirmed that dexamethasone remarkably reduces the expressions of V2R, aquaporin 2, and aquaporin 3 in the renal-collecting ducts. As a result of V2R downregulation, the expressions of glucocorticoid regulated kinase 1, apical epithelial sodium channels, and the furosemide-sensitive Na-K-2Cl cotransporter were also downregulated. These favorable effects induced by dexamethasone were mostly abolished by the glucocorticoid receptor inhibitor RU486, indicating that the aforementioned effects are glucocorticoid receptor mediated. Conclusions Glucocorticoids can reverse diluted hyponatremia via inhibiting the vasopressin receptor pathway in rats with heart failure.

Clinical studies have shown that large doses of prednisone could lower serum uric acid (SUA) in patients with decompensated heart failure (HF); however, the optimal dose of prednisone and underlying mechanisms are unknown. Thirty-eight patients with decompensated HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/day, n = 8), medium-dose (30 mg/day, n = 10), or high-dose prednisone (60 mg/day, n = 10), for 10 days. At the end of the study, only high-dose prednisone significantly reduced SUA, whereas low- and medium-dose prednisone and standard HF care had no effect on SUA. The reduction in SUA in high-dose prednisone groups was associated with a significant increase in renal uric acid clearance. In conclusion, prednisone can reduce SUA levels by increasing renal uric acid clearance in patients with decompensated HF.

Background: Recent evidence indicates that prednisone can potentiate renal responsiveness to diuretics in heart failure (HF). However, the optimal dose of prednisone is not known., Method: Thirty-eight patients with symptomatic HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/d, n = 8), medium-dose (30 mg/d, n = 10), or high-dose prednisone (60 mg/d, n = 10), for 10 days. During this time, we recorded the 24-hour urinary output and the 24-hour urinary sodium excretion, at baseline, on day 5 and day 10. We also monitored the change in the concentration of serum creatinine, angiotensin II, aldosterone, high-sensitive C-reactive protein, tumor necrosis factor-α, interleukin 1β, and interleukin 6., Results: Low-dose prednisone significantly enhanced urine output. However, the effects of medium- and high-dose prednisone on urine output were less obvious. As for renal sodium excretion, high-dose prednisone induced a more potent natriuresis than low-dose prednisone. Despite the potent diuresis and natriuresis induced by prednisone, serum creatinine, angiotensin II, and aldosterone levels were not elevated. These favorable effects were not associated with an inflammatory suppression by glucocorticoids., Conclusions: Only low-dose prednisone significantly enhanced urine output. However, high-dose prednisone induced a more potent renal sodium excretion than low-dose prednisone.

Objective: To determine the safety and efficacy of prednisone in patients with symptomatic heart failure (HF) and hyperuricemia., Methods: Prednisone therapy was administered for a short time to 191 symptomatic HF patients with hyperuricemia (serum uric acid > 7 mg/dl)., Results: Prednisone significantly reduced serum uric acid by 2.99 mg/dl (p < 0.01) and serum creatinine by 0.17 mg/dl (p < 0.01). These favorable effects were associated with a remarkable increase in urine output, improvement in renal function, and improvement in clinical status., Conclusion: Prednisone can be used safely in symptomatic HF patients with hyperuricemia.

Diuretic resistance in heart failure is defined as a state in which diuretic response is diminished or lost before the therapeutic goal of relief from congestion has been reached. Diuretic resistance is very common and is associated with poor outcomes. Over the past decade, several new drugs and devices targeting decongestion and improvement in renal function in patients with heart failure have failed to show benefit in randomized clinical trials. Glucocorticoids had been used to manage diuretic resistance before the advent of loop diuretics. More recent evidence appears to confirm that glucocorticoids may also help to overcome resistance to loop diuretics. This review tries to summarize the available evidence and potential mechanisms related to glucocorticoid therapy in patients with heart failure and its effect on diuretic resistance., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Newly emerging evidence showed that glucocorticoids could potentiate natriuretic peptides' action by increasing the density of natriuretic peptide receptor A, leading to a potent diuresis and a renal function improvement in patients with acute decompensated heart failure (ADHF). Therefore, glucocorticoid therapy may be used in patients with ADHF., Methods: One hundred two patients with ADHF were randomized to receive glucocorticoids or standard treatment. Change from baseline in serum creatinine (SCr) at day 7 and cardiovascular death within 30 days were recorded. The study was terminated early because of slow site initiation and patient enrolment., Results: Glucocorticoid therapy seemed to be well tolerated. There was a remarkable SCr reduction after 7 days treatment. The change from baseline in SCr is -0.14 mg/dL in glucocorticoid group versus -0.02 mg/dL in standard treatment group (P < 0.05). Although sample size is limited, a cardiovascular death reduction at 30 days was observed in glucocorticoid group with odds ratio of 0.26 (3 deaths in glucocorticoid vs. 10 deaths in standard treatment group, P < 0.05). The survival benefit associated with glucocorticoid therapy persisted during the follow-up. Patient-assessed dyspnea and physician-assessed global clinical status were also improved in glucocorticoid group., Conclusions: Limited data indicate that glucocorticoid therapy may be used safely in patients with ADHF in short term. Glucocorticoid therapy did not cause heart failure deterioration. Further investigations are warranted.

Background: Chronic drug interactions that exist between symptomatic congestive heart failure (CHF) therapy and pharmacologic agents used for hyperuricemia and gout are a challenging problem in clinical practice. Recent observational studies showed that prednisone can induce a potent diuresis and lower serum uric acid concentration (SUA) in CHF. We therefore designed a randomized study to compare the effect of prednisone with allopurinol on SUA in symptomatic CHF patients with hyperuricemia., Methods: Thirty-four symptomatic CHF participants with hyperuricemia (≥ 565 μmol/L) were randomized to receive prednisone (1 mg/kg/d, orally) or allopurinol (100 mg, thrice daily, orally) for 4 weeks. The primary outcome measure was change from baseline in SUA. The secondary outcome measures were change from baseline in serum creatinine levels, estimated glomerular filtration rate, daily urine output, body weight, N-terminal pro-B-type natriuretic peptide levels, physician-assessed global clinical status, and New York Heart Association functional class., Results: Both prednisone and allopurinol greatly lowered SUA rapidly. The overall SUA-lowering effect did not differ between treatment groups during the study period (P = 0.48, 2-way repeated measures analysis of variance). However, prednisone increased estimated glomerular filtration rate and daily urine output, and lowered body weights and N-terminal pro-B-type natriuretic peptide. Consequently, participants treated with prednisone had an improvement in clinical status., Conclusions: The study showed that the SUA-lowering effect of prednisone and allopurinol is similar in symptomatic CHF patients. Prednisone might be useful for short-term SUA-lowering in CHF patients with hyperuricemia., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

In heart failure, the renal responsiveness to exogenous and endogenous atrial natriuretic peptide (ANP) is blunted. The mechanisms of renal hyporesponsiveness to ANP are complex, but one potential mechanism is decreased expression of natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that glucocorticoids could produce potent diuresis and natriuresis in patients with heart failure, but the precise mechanism is unclear. In the present study, we found dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the ANP) generation in IMCD cells, which presented in a time- and dose-dependent manner as well. In rats with decompensated heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal sodium excretion. It is noteworthy that Dex dramatically lowered plasma ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486). Collectively, glucocorticoids could improve renal responsiveness to ANP by up-regulating NPR-A expression in the IMCD and induce a potent diuretic action in rats with decompensated heart failure.

The aim of the present study was to determine if prednisone, a glucocorticoid, added to conventional treatment for patients with decompensated congestive heart failure (DCHF) refractory to the conventional care, results in significant relief of congestive symptoms and improvement of clinical status. Diuretic-based strategies, as the mainstay in DCHF management, are not always effective in eliciting diuresis. However, the addition of prednisone to standard care may induce potent diuresis in this clinical setting. Thirty-five patients with DCHF were enrolled in the study, and prednisone (1 mg/kg/day with maximum dosage of 60 mg/day) was added to the standard treatment. Primary endpoints were the effects on daily urine volume, patient and physician assessed dyspnea and global clinical status, and changes in renal function. The addition of prednisone induced potent diuresis with time. As a result of the diuresis, congestive symptoms improved markedly in 80% and global clinical status improved markedly in 68.6% of the DCHF patients at the end of the study (P < 0.001). The change in serum creatinine from baseline was -12.21 micromol/L (P < 0.05). Adding prednisone to conventional care in the patients with refractory DCHF induced potent diuresis accompanied by a dramatic relief of congestive symptoms and improvements in clinical status and renal function.

Background: Refractory congestive heart failure (CHF) with diuretic resistance is life-threatening and predicts a short life expectancy. Glucocorticoids have been proven to have potent diuretic effects in animal studies; however, their efficacy in CHF patients with diuretic resistance is not known., Methods: Thirteen CHF patients with significant volume overload and diuretic resistance who failed to respond to a conventional sequential nephron blockade therapeutic strategy; that is, the coadministration of a thiazide (hydrochlorothiazide) and spironolactone, in combination with loop diuretics, were studied. Prednisone (1 mg/kg daily) was then added to standard care, with other medications unchanged, to determine diuretic efficacy in these CHF patients. Variables included body weight, urine volume, serum electrolytes and renal function., Results: Adding prednisone resulted in striking diuresis with a mean (+/- SD) body weight reduction of 9.39+/-3.09 kg. Prednisone significantly decreased serum creatinine by 52.21+/-48.68 mumol/L and increased glomerular filtration rate by 33.63+/-15.87 mL/min/1.73 m(2) compared with baseline. All patients were discharged from hospital with improved clinical status and renal function, and 11 patients remained alive in the long term. The main side effect of prednisone appeared to be hyperglycemia in diabetic patients., Conclusions: The present study demonstrated that prednisone can rapidly eliminate volume overload and improve clinical status and renal function in CHF patients with diuretic resistance. Further prospective randomized clinical studies are warranted to confirm its clinical efficacy.

Unlabelled: Animal studies showed glucocorticoids could specifically dilate renal vasculature, regulate synthesis and release of atrial natriuretic peptide (ANP), upregulate ANP receptors on vascular endothelial cells, and thus have potent potentiating diuresis and natriuresis effects in animal studies; however, their diuretic efficacy in humans is yet to be known. Therefore, we designed this randomized, double- blind, placebo-controlled, clinical study to determine the diuretic efficacy of prednisone, a glucocorticoid, in patients with congestive heart failure (CHF)., Methods: Twenty clinically stable patients with CHF without overt fluid retention were randomized to a prednisone group or placebo group. Prednisone (1 mg/kg/day with a maximum dose of 60 mg/day) was added to standard care for 7 days, leaving other medications unchanged. Variables included urine volume and electrolytes, serum electrolytes, and change from baseline in serum creatinine., Results: Adding prednisone resulted in striking diuresis and natriuresis with time. As compared with the placebo group, the maximum of mean daily urine volume was 810.5 mL larger than those in the placebo group (95% confidence intervals [CI] 276.25 to 1344.86, P < 0.05). The maximum mean daily sodium excretion was 123.8 mmol higher than those patients given placebo (95% CI 11.4 to 236.2, P < 0.05). The placebo-corrected effect on change from baseline in serum creatinine was -19.5 mumol/L (95% CI -7.4 to -31.6, P < 0.01), favoring prednisone., Conclusions: This pilot study showed that prednisone had potent potentiating diuretic effects in patients with heart failure and might improve renal function in the same time. Further prospective randomized clinical studies are warranted to determine the preferable dose and its efficacy in decompensated congestive heart failure.