GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement.

CONTEXT: GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15. OBJECTIVE: To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels. METHODS AND RESULTS: We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison's disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison's cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison's disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001. CONCLUSIONS: GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency

Supplementary data: GDF15 is elevated in conditions of glucocorticoid deficiency and is modulated by glucocorticoid replacement

The file consists of supplementary tables containing the individual participant GDF15 measurements for the four study cohorts reported in the associated manuscript

Circulating progenitor cells and their interaction with platelets in patients with an acute coronary syndrome

CD34+ cells expressing KDR (CD34+/KDR+) represent a small proportion of circulating progenitor cells that have the capacity to interact with platelets and to differentiate into mature endothelial cells, thus contributing to vascular homeostasis and regeneration as well as to re-endothelialization. We investigated the levels of CD34+ and CD34+/KDR+ progenitor cells as well as their interaction with platelets in acute coronary syndrome (ACS) patients before the initiation (baseline) of their treatment with a P2Y12 receptor antagonist, and at 5-days post-treatment (follow-up). Sixty-seven consecutive ACS patients and thirty healthy subjects (controls) participated in the study. On admission, all patients received 325 mg aspirin, followed by 100 mg/day and then were loaded either with 600 mg clopidogrel or 180 mg ticagrelor, followed by 75 mg/day (n = 36) or 90 mg × 2/day (n = 31), respectively. The levels of circulating CD34+ and CD34+/KDR+ progenitor cells, as well as their interaction with platelets, were determined by flow cytometry, before and after activation with ADP, in vitro. The circulating levels of CD34+ and CD34+/KDR+ cells in both patient groups at baseline were lower compared with controls while they were significantly increased at 5-days of follow-up in both groups, this increase being more pronounced in the ticagrelor group. The platelet/CD34+ (CD61+/CD34+) conjugates were higher at baseline and reduced at follow-up while the platelet/KDR+ (CD61+/KDR+) conjugates were lower at baseline and increased at follow-up, both changes being more pronounced in the ticagrelor group. ADP activation of control samples significantly increased the KDR expression by CD34+ cells and the CD61+/KDR+ conjugates, these parameters being unaffected in patients at baseline but increased at follow-up. Short-term dual antiplatelet therapy in ACS patients restores the low platelet/KDR+ conjugates and CD34+ cell levels and improves the low membrane expression levels of KDR in these cells, an effect being more pronounced in ticagrelor-treated patients. This may represent a pleiotropic effect of antiplatelet therapy towards vascular endothelial regeneration