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- Pelletier, F., et al.
(författare)
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Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
- 2021
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 106:2
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Tidskriftsartikel (refereegranskat)abstract
- Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting: This was a multicenter retrospective study using information collected from 3 predominant centers. Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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| 4. |
- Ferreira, J. P., et al.
(författare)
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Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial
- 2019
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 21:3, s. 345-351
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Tidskriftsartikel (refereegranskat)abstract
- Background Current heart failure guidelines recommend target eplerenone dose of 50 mg/day. We have examined the effect of different eplerenone doses based on pre-specified renal function stratification in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Methods and results In EMPHASIS-HF, the target dose of eplerenone/placebo was stratified at randomization according to estimated glomerular filtration rate (eGFR): 50 mg/day if eGFR >= 50 mL/min/1.73m(2) and <= 25 mg/day if eGFR 30-49mL/min/1.73m(2). Patients remained within these dose ranges during the trial (as per stratification). The primary outcome was a composite of heart failure hospitalization or cardiovascular mortality. Eplerenone was superior to placebo within each respective eGFR stratum [eplerenone vs. placebo in the eGFR >= 50 mL/min/1.73m2 stratum: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45-0.74; and eplerenone vs. placebo in the eGFR 30-49mL/min/1.73m(2) stratum: HR 0.62, 95% CI 0.49-0.78; P-interaction = 0.89]. Despite receiving lower eplerenone doses, patients in the eGFR 30-49mL/min/1.73m(2) stratum more often had hyperkalaemia, renal failure events, and drug discontinuation. Conclusion In EMPHASIS-HF the eplerenone dose was stratified according to renal function and the treatment effect was not influenced by renal function: 25 mg/day in patients with eGFR 30-49mL/min/1.73m(2) was as effective as 50 mg/day in patients with eGFR> = 50 mL/min/1.73m(2). However, patients with impaired renal function experienced more adverse events, despite reveiving lower eplerenone doses. Current guidelines do not recommend tailoring the dose of eplereone according to renal function but the current data suggest they should.
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| 6. |
- Ferreira, J. P., et al.
(författare)
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Impact of Insulin Treatment on the Effect of Eplerenone: Insights From the EMPHASIS-HF Trial
- 2021
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Ingår i: Circulation-Heart Failure. - : Ovid Technologies (Wolters Kluwer Health). - 1941-3289 .- 1941-3297. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms). METHODS: The primary outcome was the composite of heart failure hospitalization or cardiovascular death. Cox models with treatment-by-diabetes subgroup interaction terms were used. RESULTS: The median follow-up was 21 (10-33) months. Of the 2737 patients included, 623 (23%) had non-insulin-treated diabetes, 236 (9%) had insulin-treated diabetes and 1878 did not have diabetes. Patients with insulin-treated diabetes were younger, more often women, with higher body mass index, waist circumference, more frequent ischemic heart failure cause, impaired kidney function, and longer diabetes duration. Compared with patients without diabetes, those with insulintreated diabetes had a 2-fold higher risk of having a primary outcome event. The hazard ratio (95% CI) for the effect of eplerenone, compared with placebo, on the primary outcome was 0.31 (0.19-0.50) in insulin-treated diabetes, 0.69 (0.500.93) in non-insulin-treated diabetes, and 0.72 (0.58-0.88) in patients without diabetes; interaction P=0.007. The annualized number needed-to-treat-to-benefit with regards to the primary outcome was 3 (95% CI, 3-4) in patients with insulin-treated diabetes, 16 (13-19) in patients with diabetes not receiving insulin, and 26 (24-28) in patients without diabetes. CONCLUSIONS: Patients with insulin-treated diabetes experienced a greater benefit from eplerenone than those with diabetes not treated with insulin and people without diabetes.
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- Khan, S. S., et al.
(författare)
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Changes in Serum Potassium Levels During Hospitalization in Patients With Worsening Heart Failure and Reduced Ejection Fraction (from the EVEREST Trial)
- 2015
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 115:6, s. 790-796
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Tidskriftsartikel (refereegranskat)abstract
- Both hyperkalemia and hypokalemia may be related to heart failure (HF) therapy and are associated with adverse outcomes. Abnormalities in serum potassium levels in hospitalized patients with HF and reduced ejection fraction (EF) have not been previously investigated. A post hoc analysis was performed in 1,907 hospitalized patients with worsening HF and reduced EF in the placebo arm of the Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST) trial. Serum potassium was measured at randomization and at discharge or day 7. The co-primary end points were all-cause mortality (ACM) and cardiovascular mortality or the first HF hospitalization (CVM + HFH). The association between inhospital change in potassium levels and time to outcomes was evaluated using multivariate Cox regression models. Study participants had a mean age of 65.6 +/- 12.0 years and were on optimal guideline-directed medical therapies, including beta blockers (77%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (85%), and aldosterone antagonists (55%). Baseline potassium concentration was 4.3 +/- 0.6 mEq/l, and hyperkalemia or hypokalemia was seen in 6.5% of the participants. On average, serum potassium level increased by 0.21 +/- 0.66 mEq/l, p < 0.0001, during hospitalization. Inhospital potassium change was not associated with either the primary or the secondary end point over a median follow-up of 9.9 months. In conclusion, in patients with reduced EF hospitalized for worsening HF, serum potassium abnormalities are common at baseline (within 48 hours of admission) and potassium levels increase during hospitalization, despite aggressive diuretic therapy. However, they are not associated with all-cause or CVM or HFH. Inhospital changes in potassium may limit the implementation of evidence-based therapies such as mineralocorticoid receptor antagonists. (C) 2015 Elsevier Inc. All rights reserved.
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| 10. |
- Zannad, F., et al.
(författare)
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Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice
- 2012
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 33:22, s. 2782-2795
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Tidskriftsartikel (refereegranskat)abstract
- Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF-REF.
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