Translational evidence of prothrombotic and inflammatory endothelial damage in Cushing syndrome after remission

Aranda, Gloria; Fernández-Ruiz, Rebeca; Palomo, Marta; Romo, Mónica; Mora, Mireia; Halperín, Irene; Casals, Gregori; Enseñat, Joaquim; Vidal, Òscar; Díaz‐Ricart, Maribel; Hanzu, Felicia A.

doi:10.1111/cen.13521

Cited by 17 publications

(3 citation statements)

References 36 publications

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“…9,10 It is worth noting that the cardiometabolic syndrome still progresses in some patients despite achieving long-term remission after medical treatment. 11 Currently, there is no ideal treatment strategy for preventing tissue-specific consequences of hypercortisolism.…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin improves chronic hypercortisolism-induced abnormal myocardial structure and cardiac function in mice

Zhang

Zhong

et al. 2020

Therapeutic Advances in Chronic Disease

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Background: Chronic exposure to excess glucocorticoids is frequently associated with a specific cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has beneficial effects as it aids in the reduction of heart failure and cardiovascular mortality in hospitalized patients. The aim of this study was to investigate the effects of empagliflozin on chronic hypercortisolism-induced myocardial fibrosis and myocardial dysfunction in mice. Methods: Male C57BL/6J mice (6 weeks old) were randomized to control, corticosterone (CORT), and empagliflozin + CORT groups. After 4 weeks of administration, heart structure and function were evaluated by echocardiography, and peripheral blood and tissue samples were collected. Expressions of Ccl2, Itgax, Mrc1, and Adgre1 mRNA in heart tissue were evaluated by RT-PCR, and signal transducer and activator of transcription 3 (STAT3) and Toll-like receptor 4 (TLR4) protein expression were analyzed by Western blotting. Results: Empagliflozin effectively reduced body weight, liver triglyceride, visceral adipose volume, and uric acid in CORT-treated mice. Left ventricular hypertrophy and cardiac dysfunction were improved significantly, phosphorylated STAT3 and TLR4 were alleviated, and macrophage infiltration in the myocardium was inhibited after administration of empagliflozin in CORT-treated mice. Conclusion: Empagliflozin has beneficial effects on specific cardiomyopathy associated with CORT, and the results provide new evidence that empagliflozin might be a potential drug for the prevention of this disease.

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Section: Introductionmentioning

confidence: 99%

Empagliflozin improves chronic hypercortisolism-induced abnormal myocardial structure and cardiac function in mice

Zhang

Zhong

et al. 2020

Therapeutic Advances in Chronic Disease

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“…Although endogenous CS is a rare disease (Feelders et al 2015), an estimated 1-2% of the global adult population receives long-term treatment with GCs for a broad spectrum of inflammatory and autoimmune diseases (van Staa 2000, Overman et al 2013 with similar cardiometabolic side effects. Despite significant improvements in CS phenotype after medical treatment, cardiometabolic risk remains increased in these patients, even after long-term remission (Colao et al 1999, Pivonello et al 2005, Aranda et al 2018. Specifically, several studies in humans have reported persistent abdominal fat accumulation, insulin resistance and systemic low-grade inflammation (Barahona et al 2009, Geer et al 2012, Wagenmakers et al 2015, Shah et al 2017.…”

Section: Introductionmentioning

confidence: 99%

Chronic hypercortisolism causes more persistent visceral adiposity than HFD-induced obesity

García-Eguren

Giró

Romero

et al. 2019

Journal of Endocrinology

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Excessive and prolonged glucocorticoid (GC) exposure, resulting from either prescribed or endogenous hypercortisolism, is associated with a high cardiovascular and metabolic burden (Cushing’s syndrome). Although previous studies in humans and mice have reported heterogeneous data about the persistence of metabolic syndrome features after remission of hypercortisolism, there is still controversy as to whether this is due to the deleterious changes induced by GCs during active disease or the result of various other factors interfering in the recovery period. In order to study metabolic effects after remission, we used a reversible mouse model of corticosterone (CORT) (100 µg/mL) administration in drinking water for 5 weeks, followed by a 10-week recovery period. We compared CORT-induced effects at these time points with a high-fat diet-treated group (HFD 45%) and a vehicle group (VEH). Plasma CORT, 11β-HSD activity, food intake, glucose levels, interscapular brown adiposity, hepatic triglycerides and muscle mass were found altered during CORT treatment but normalized after recovery. Although hyperinsulinemia and insulin resistance were increased during CORT and HFD treatment, insulin homeostasis remained altered following the recovery period only in CORT-treated mice. Subcutaneous and visceral adipose tissues (SAT and VAT) were enlarged during HFD and CORT treatment as measured by MRI. However, increased muscle lipid content, adiposity and macrophage infiltration in VAT were only present in the CORT group following recovery. Taken together, CORT-induced insulin alterations were more potent than HFD-induced ones during the same period of treatment, and also more persistent long term. Moreover, we demonstrated that CORT treatment induces more long-lasting VAT enlargement than HFD.

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“…There are numerous reports on the elevation of vWF in patients with CS as compared with control subjects ( 4 , 7 , 46 – 50 ), comparison of vWF in active phase and after treatment ( 38 , 48 , 51 ), and the association between vWF promoter polymorphism with vWF level ( 35 , 36 , 52 ). The recent meta-analysis demonstrated no linear relationship between vWF level and number of thrombotic events ( 2 ); however, the logistic regression was not corrected for the blood type.…”

Section: Resultsmentioning

confidence: 99%

The thrombotic risk in Cushing’s syndrome—questions, answers, and the algorithm to consider in its assessment: part I—thrombotic risk not related to surgery

Bryk-Wiązania,

Minasyan,

Świątkowska-Stodulska

et al. 2024

Front. Endocrinol.

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IntroductionRecently, it has been reported that there is a great diversity in strategies used for thromboprophylaxis in patients with Cushing’s syndrome (CS). An aim of this review was to discuss these practices in light of the existing data on the thrombotic risk in patients with CS and guidelines for medically ill patients.MethodsThe four relevant topics and questions on thrombotic risk in CS were identified. The current guidelines on prevention and diagnosis of venous thromboembolism (VTE) were reviewed for the answers. An algorithm to consider in the assessment of the thrombotic risk in patients with CS was proposed.ResultsTo address both generic and CS-specific risk factors for VTE, the algorithm includes the stepwise approach consisting of Padua Score, urine free cortisol, and CS-VTE score, with no indication for routine thrombophilia testing in the prediction of an index VTE episode. Having confirmed VTE, selected patients require thrombophilia testing to aid the duration of anticoagulant treatment. The separate part of the algorithm is devoted to patients with ectopic adrenocorticotropic hormone syndrome in whom exclusion of VTE precedes introducing routine thromboprophylaxis to prevent VTE. The cancer-related VTE also prompts thromboprophylaxis, with the possible vessel invasion. The algorithm presents a unifactorial and multifactorial approach to exclude high-bleeding risks and safely introduce thromboprophylaxis with low-molecular-weight heparin.SummaryOur article is the first to present an algorithm to consider in the thrombotic risk assessment among patients with Cushing’s syndrome as a starting point for a broader discussion in the environment. A plethora of factors affect the VTE risk in patients with CS, but no studies have conclusively evaluated the best thromboprophylaxis strategy so far. Future studies are needed to set standards of care.

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Translational evidence of prothrombotic and inflammatory endothelial damage in Cushing syndrome after remission

Abstract: The sera of premenopausal women with CS in remission, without atherothrombotic disease, contain circulatory endothelial deleterious factors with a direct thrombogenic and pro-inflammatory endothelial effect that could increase cardiovascular risk.

Cited by 17 publications

References 36 publications

Empagliflozin improves chronic hypercortisolism-induced abnormal myocardial structure and cardiac function in mice

Empagliflozin improves chronic hypercortisolism-induced abnormal myocardial structure and cardiac function in mice

Chronic hypercortisolism causes more persistent visceral adiposity than HFD-induced obesity

The thrombotic risk in Cushing’s syndrome—questions, answers, and the algorithm to consider in its assessment: part I—thrombotic risk not related to surgery

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