Search

Purpose: Cushing’s syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS. Methods: This was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up. Results: Sixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p= 0.027; p= 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p= 0.035; p= 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p= 0.056; p= 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p< 0.001) and no differences in lipid levels or blood pressure. Conclusion: CS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors.

It is estimated that 2% to 3% of the population are currently prescribed systemic or topical glucocorticoid treatment. The potent anti-inflammatory action of glucocorticoids to deliver therapeutic benefit is not in doubt. However, the side effects associated with their use, including central weight gain, hypertension, insulin resistance, type 2 diabetes (T2D), and osteoporosis, often collectively termed iatrogenic Cushing's syndrome, are associated with a significant health and economic burden. The precise cellular mechanisms underpinning the differential action of glucocorticoids to drive the desirable and undesirable effects are still not completely understood. Faced with the unmet clinical need to limit glucocorticoid-induced adverse effects alongside ensuring the preservation of anti-inflammatory actions, several strategies have been pursued. The coprescription of existing licensed drugs to treat incident adverse effects can be effective, but data examining the prevention of adverse effects are limited. Novel selective glucocorticoid receptor agonists and selective glucocorticoid receptor modulators have been designed that aim to specifically and selectively activate anti-inflammatory responses based upon their interaction with the glucocorticoid receptor. Several of these compounds are currently in clinical trials to evaluate their efficacy. More recently, strategies exploiting tissue-specific glucocorticoid metabolism through the isoforms of 11β-hydroxysteroid dehydrogenase has shown early potential, although data from clinical trials are limited. The aim of any treatment is to maximize benefit while minimizing risk, and within this review we define the adverse effect profile associated with glucocorticoid use and evaluate current and developing strategies that aim to limit side effects but preserve desirable therapeutic efficacy.Graphical Abstract

L’ottimizzazione della terapia con mineralcorticoidi in pazienti con insufficienza surrenalica primaria non ha ancora trovato consenso universale. Questa rassegna riporta i dati di una vasta coorte di pazienti affetti da insufficienza surrenalica primaria con l’obiettivo di esplorare la relazione tra la dose sostitutiva dei mineralcorticoidi (MC), la concentrazione plasmatica di renina (CPR) e variabili cliniche ambulatoriali (elettroliti, pressione sanguigna, PA, e parametri antropometrici) al fine di identificare marcatori utili per guidare la titolazione della dose MC. I risultati hanno mostrato un’estrema variabilità nei valori di CPR e nella dose di MC. Nell’analisi univariata, la dose di MC era direttamente proporzionale alla CPR ma non correlava con i livelli di PA. Utilizzando modelli di regressione multipla, il sodio era l’unica variabile utile a predire la CPR. Nell’analisi longitudinale, la variazione della dose di MC era correlata alla variazione dei livelli sierici di potassio ma non alla PA o alla CPR. In conclusione, la relazione tra la dose di MC e la CPR è complessa e, pertanto, la titolazione dei MC non dovrebbe essere basata solo sulla normalizzazione della CPR, ma anche su parametri clinici come la PA e la concentrazione di elettroliti.

This study evaluates the predictive value of copeptin for syndrome of inappropriate antidiuresis (SIAD) postpituitary transsphenoidal surgery (TSS). Data from 133 consecutive patients undergoing TSS (November 2017–October 2022) at Oxford University Hospitals NHS trust are presented in this retrospective study. Logistic regression (LR) and receiver operating characteristic (ROC) curves were performed to evaluate the diagnostic utility of copeptin. The Mann–Whitney U test was used to compare copeptin levels between the SIAD and no SIAD groups. Fourteen patients (10.8%) developed SIAD. Copeptin was available in 121, 53 and 87 patients for Days 1, 241 and 8 post‐TSS, respectively. LR for Day 1 copeptin to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 42 0.84–1.20, p= .99), area under‐ROC curve (AUC) was 0.49; Day 2 copeptin OR was 0.65 (95%CI 0.39–1.19, 43 p= .77), AUC was 0.57 LR for Day 1 sodium to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 0.85–1.21, p= .99), AUC was 0.50. In conclusion, our data provide no evidence for copeptin as a predictive marker for post‐TSS SIAD. This study evaluates the predictive value of copeptin for syndrome of inappropriate antidiuresis (SIAD) postpituitary transsphenoidal surgery (TSS). Data from 133 consecutive patients undergoing TSS (November 2017–October 2022) at Oxford University Hospitals NHS trust are presented in this retrospective study. Our data provide no evidence for copeptin as a predictive marker for post‐TSS SIAD.

Secondary adrenal insufficiency is a potential complication of transsphenoidal adenomectomy (TSA). Most centers test recovery of the hypothalamo-pituitary-adrenal (HPA) axis after TSA, but, to our knowledge, there are no data predicting likelihood of recovery or the frequency of later recovery of HPA function.

In patients with reversible causes of adrenal insufficiency, a 30-minute cortisol level of >350 nmol/L (12.7 g/dL) during a short Synacthen test conveys a 99% chance of HPA axis recovery within 4 years.

We compared multiple-times-a-day vs once-daily modified-release hydrocortisone in adrenal insufficiency and found a significant effect on the expression of several clock-related genes.

Background: Diabetic nephropathy (DN) is currently the most common cause of end-stage renal disease (ESRD). Although nowadays much is known about its classification, pathogenesis, clinical manifestations and evolution, to date we are not yet able to stop the natural progression of nephropathy in diabetic patients. Methods: Treatment options are: lifestyle change with close blood pressure monitoring and tight glycemic control. The most common therapies adopted for this condition are Angiotensing Converting Enzyme-inhibitors (ACEi). However these drugs are able to block the progression of renal damage only in a small proportion of patients. In the remaining, DN progresses and may evolve into ESRD. Conclusion: The purpose of this review is to summarize the “state of art” of current novel therapeutic strategies to stem this debilitating kidney disease.

Context:Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients.Objective:To investigate whether PDE5i affect visceral adipose tissue (VAT), specifically epicardial fat (epicardial adipose tissue [EAT]), and what mechanism is involved, using microarray-based profiling of pharmacologically modulated microRNA (miRNAs).Design:Randomized, double-blind, placebo-controlled study in type 2 diabetes.Patients and Intervention:A total of 59 diabetic patients were randomized to receive 100-mg/d sildenafil or placebo for 12 weeks. Fat biopsies were collected in a subgroup of patients. In a parallel protocol, db/dbmice were randomized to 12 weeks of sildenafil or vehicle, and VAT was collected.Main Outcomes and Measures:Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT.Results:Compared with placebo, sildenafil reduced waist circumference (P= .024) and EAT (P= .045). Microarray analysis identified some miRNAs differentially regulated by sildenafil, including down-regulation of miR-22-3p, confirmed by real-time quantitative PCR (P< .001). Sildenafil's modulation of miR-22-3p expression was confirmed in vitro in HL1 cardiomyocytes. Up-regulation of SIRT1, a known target of miR-22-3p, was found in both serum and sc fat in sildenafil-treated subjects. Compared with vehicle, 12-week sildenafil treatment down-regulated miR-22-3p and up-regulated Sirtuin1 (SIRT1) gene expression in VAT from db/dbmice, shifting adipose tissue cell composition toward a less inflamed profile.Conclusions:Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.

Cyclic GMP–phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c < 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (−3.40°, −5.96; −0.84, P= 0.011) and fiber shortening (−1.19%, −2.24; −0.14, P= 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14++CD16−monocytes reduced, and Tie2+monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.