Jean Wigham

Prospective, nonrandomized study to evaluate endovascular repair of pararenal and thoracoabdominal aortic aneurysms using fenestrated-branched endografts based on supraceliac sealing zones

Purpose: To investigate outcomes of manufactured fenestrated and branched endovascular aortic repair (F‐BEVAR) endografts based on supraceliac sealing zones to treat pararenal aortic aneurysms and thoracoabdominal aortic aneurysms (TAAAs). Methods: A total of 127 patients (91 male; mean age, 75 ± 10 years old) were enrolled in a prospective, nonrandomized single‐center study using manufactured F‐BEVAR (November 2013‐March 2015). Stent design was based on supraceliac sealing zone in all patients with ≥ four vessels in 111 (89%). Follow‐up included clinical examination, laboratory studies, duplex ultrasound, and computed tomography imaging at discharge, 1 month, 6 months, and yearly. End points adjudicated by independent clinical event committee included mortality, major adverse events (any mortality, myocardial infarction, stroke, paraplegia, acute kidney injury, respiratory failure, bowel ischemia, blood loss >1 L), freedom from reintervention, and branch‐related instability (occlusion, stenosis, endoleak or disconnection requiring reintervention), target vessel patency, sac aneurysm enlargement, and aneurysm rupture. Results: There were 47 pararenal, 42 type IV, and 38 type I‐III TAAAs with mean diameter of 59 ± 17 mm. A total of 496 renal‐mesenteric arteries were incorporated by 352 fenestrations, 125 directional branches, and 19 celiac scallops, with a mean of 3.9 ± 0.5 vessels per patient. Technical success of target vessel incorporation was 99.6% (n = 493/496). There were no 30‐day or in‐hospital deaths, dialysis, ruptures or conversions to open surgical repair. Major adverse events occurred in 27 patients (21%). Paraplegia occurred in two patients (one type IV, one type II TAAAs). Follow‐up was >30 days in all patients, >6 months in 79, and >12 months in 34. No patients were lost to follow‐up. After a mean follow‐up of 9.2 ± 7 months, 23 patients (18%) had reinterventions (15 aortic, 8 nonaortic), 4 renal artery stents were occluded, five patients had type Ia or III endoleaks, and none had aneurysm sac enlargement. Primary and secondary target vessel patency was 96% ± 1% and 98% ± 0.7% at 1 year. Freedom from any branch instability and any reintervention was 93% ± 2% and 93% ± 2% at 1 year, respectively. Patient survival was 96% ± 2% at 1 year for the entire cohort. Conclusions: Endovascular repair of pararenal aortic aneurysms and TAAAs, using manufactured F‐BEVAR with supraceliac sealing zones, is safe and efficacious. Long‐term follow‐up is needed to assess the impact of four‐vessel designs on device‐related complications and progression of aortic disease.

Endovascular repair of thoracoabdominal aortic aneurysms using fenestrated and branched endografts

Purpose: The study purpose was to review the outcomes of patients treated for thoracoabdominal aortic aneurysms using endovascular repair with fenestrated and branched stent‐grafts in a single center. Methods: We reviewed the clinical data of the first 185 consecutive patients (134 male; mean age, 75 ± 7 years) treated for thoracoabdominal aortic aneurysms using fenestrated and branched stent‐grafts. Graft design evolved from physician‐modified endografts (2007‐2013) to off‐the‐shelf or patient‐specific manufactured devices in patients enrolled in a prospective physician‐sponsored investigational device exemption protocol (NCT 1937949 and 2089607). Outcomes were reported for extent IV and extent I to III thoracoabdominal aortic aneurysms, including 30‐day mortality, major adverse events, patient survival, primary target vessel patency, and reintervention. Results: A total of 112 patients (60%) were treated for extent IV thoracoabdominal aortic aneurysms, and 73 patients (40%) were treated for extent I to III thoracoabdominal aortic aneurysms. Demographics and cardiovascular risk factors were similar in both groups. A total of 687 renal‐mesenteric arteries (3.7 vessels/patient) were targeted by 540 fenestrations and 147 directional branches. Technical success was 94%. Thirty‐day mortality was 4.3%, including a mortality of 1.8% for extent IV and 8.2% for extent I to III thoracoabdominal aortic aneurysms (P = .03). Mortality decreased in the second half of clinical experience from 7.5% to 1.2%, including a decrease of 3.3% to 0% for extent IV thoracoabdominal aortic aneurysms (P = .12) and 15.6% to 2.4% for extent I to III thoracoabdominal aortic aneurysms (P = .04). Early major adverse events occurred in 36 patients (32%) with extent IV thoracoabdominal aortic aneurysms and 26 patients (36%) with extent I to III thoracoabdominal aortic aneurysms, including spinal cord injury in 2 patients (1.8%) and 4 patients (3.2%), respectively. Mean follow‐up was 21 ± 20 months. At 5 years, patient survival (56% and 59%, P = .37) and freedom from any reintervention (50% and 53%, P = .26) were similar in those with extent IV and extent I to III thoracoabdominal aortic aneurysms. Primary patency was 93% at 5 years. Conclusions: Endovascular repair of thoracoabdominal aortic aneurysms can be performed with high technical success and low mortality and morbidity. However, the need for secondary reinterventions and continued graft surveillance represents major limitations compared with results of conventional open surgical repair. Long‐term follow‐up is needed before the widespread use of these techniques in younger or lower‐risk patients.

Estradiol, but not testosterone, heightens cortisol-mediated negative feedback on pulsatile ACTH secretion and ACTH approximate entropy in unstressed older men and women

How sex steroids modulate glucocorticoid feedback on the hypothalamic-pituitary-corticotrope (HPC) unit is controversial in humans. We postulated that testosterone (T) in men and estradiol (E2) in women govern unstressed cortisol-mediated negative feedback on ACTH secretion. To test this hypothesis, 24 men and 24 women age 58 ± 2.4 yr were pretreated with leuprolide and either sex steroid (E2 in women, T in men) or placebo addback. Placebo or ketoconazole (KTCZ) was administered overnight to inhibit adrenal steroidogenesis during overnight 14-h intravenous infusions of saline or cortisol in a continuous versus pulsatile manner to test for feedback differences. ACTH was measured every 10 min during the last 8 h of the infusions. The main outcome measures were mean ACTH concentrations, pulsatile ACTH secretion, and ACTH approximate entropy (ApEn). ACTH concentrations were lower in women than men (P < 0.01), and in women in the E2+ compared with E2- group under both continuous (P = 0.01) and pulsatile (P = 0.006) cortisol feedback, despite higher cortisol binding globulin and lower free cortisol levels in women than men (P < 0.01). In the combined groups, under both modes of cortisol addback, ACTH concentrations, pulsatile ACTH secretion, and ACTH secretory-burst mass correlated negatively and univariately with E2 levels (each P < 0.005). E2 also suppressed ACTH ApEn (process randomness) during continuous cortisol feedback (P = 0.004). T had no univariate effect but was a positive correlate of ACTH when assessed jointly with E2 (negative) under cortisol pulses. In conclusion, sex steroids modulate selective gender-related hypothalamic-pituitary adrenal-axis adaptations to cortisol feedback in unstressed humans.

Outcomes of total percutaneous endovascular aortic repair for thoracic, fenestrated, and branched endografts

OBJECTIVE Percutaneous endovascular aortic repair (PEVAR) has been increasingly used to treat infrarenal abdominal aortic aneurysms, but few studies have evaluated the results in complex aortic aneurysms. We reviewed the technical success and clinical outcomes of PEVAR using large-diameter sheaths for the treatment of complex aortic aneurysms with thoracic, fenestrated, and branched stent grafts. METHODS The clinical data of patients who underwent total PEVAR for descending thoracic aneurysm, thoracoabdominal aortic aneurysm, pararenal, and aortoiliac aneurysms using thoracic, fenestrated, and branched stent grafts between 2009 and 2014 were reviewed. Repairs with fenestrated-branched stent grafts were performed using commercially available or investigational devices under a physician-sponsored investigational device protocols. Percutaneous closure was performed using ultrasound guidance and two Perclose devices (Abbott Vascular, Santa Clara Calif) per femoral puncture site. End points were technical success, access-related complications, morbidity, and mortality. RESULTS There were 102 patients, 77 male and 25 female, with a mean age of 75 ± 8 years. Aneurysm extent was pararenal in 48 patients (47%), thoracoabdominal aortic aneurysm in 27 (26%), descending thoracic aneurysm in 19 (19%), and aortoiliac in 8 (8%). Fenestrated or branched endografts, or both, were placed in 72 patients (71%). Total percutaneous closure was performed in 170 femoral arteries using ≥20F-diameter sheaths in 163 (96%). Technical success was obtained in 161 femoral arteries (95%). There were no factors associated with technical failure. Access-related complications occurred in five patients (5%), including femoral artery thrombosis in three (3%), and retroperitoneal hematoma or pseudoaneurysm in one patient each (1%). There were no 30-day deaths. Freedom from access-related complications was 97% ± 1% at 30 days and 1 year. No access-related complications occurred >30 days. CONCLUSIONS Total percutaneous technique can be safely performed with a high technical success rate and low rate of access complications in patients with thoracic and complex aortic disease requiring large-diameter sheaths. The rate of access-related complications (5%) is similar to that reported for PEVAR of infrarenal abdominal aortic aneurysms using smaller-profile devices.

Gender determines ACTH recovery from hypercortisolemia in healthy older humans

OBJECTIVE Available clinical data raise the possibility that stress-adaptive mechanisms differ by gender. However, this notion has not been rigorously tested in relation to cortisol-mediated negative feedback. MATERIALS/METHODS Degree of ACTH inhibition during and recovery from an experimental cortisol clamp was tested in 20 healthy older subjects (age 60±2.2 y). Volunteers received oral placebo or ketoconazole (KTCZ) to inhibit adrenal steroidogenesis along with i.v. infusions of saline or a low vs high physiological dose of cortisol in a prospectively randomized double-blind, placebo-controlled design. ACTH and cortisol concentrations were measured every 10 min during the feedback-clamp phase and thereafter (recovery or escape phase). Corticosteroid-binding globulin (CBG) was measured, and free cortisol concentrations were calculated. RESULTS Gender did not determine mean ACTH concentrations during the saline or cortisol feedback-clamp phases per se. However, women had markedly impaired ACTH recovery after stopping both low- and high-dose cortisol infusions compared with men (P=0.005, KTCZ/low-dose cortisol arm; and P=0.006, KTCZ/high-dose cortisol arm). Decreased ACTH recovery in women was accompanied by lower total and free cortisol concentrations, pointing to heightened feedback inhibition of hypothalamo-pituitary drive of ACTH secretion as the main mechanism. CONCLUSIONS In summary, gender or a factor related to gender, such as sex steroids or body composition, determines recovery of ACTH secretion from cortisol-enforced negative feedback. Attenuated ACTH recovery in post-menopausal women may have relevance to sex differences in stress-related adaptations.

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade

Gonadotrophin-releasing hormone (GnRH) pulsatility is required for optimal luteinizing hormone (LH) secretion, but whether LH pulsatility is required for physiological testosterone (T) secretion is not known. To test the postulate that pulses of recombinant human (rh) LH stimulate greater T secretion than continuous infusion of the same dose, a potent selective GnRH antagonist was administered overnight to 19 healthy men ages 18-49 yr. Subjects then received saline or rhLH intravenously continuously or as 6-min pulses intravenously every 1 or 2 h at the same total dose. Blood was sampled every 10 min for 10 h to quantify T responses. For the four interventions, the descending rank order of mean LH and mean T concentrations was 1-h = 2-h rhLH pulses > continuous rhLH > saline (P < 10(-3)). Plateau LH and T concentrations correlated positively (R(2) = 0.943, P = 0.029) as did LH concentrations and LH half-lives (R(2) = 0.962, P = 0.019). Percentage pulsatile T secretion assessed by deconvolution analysis (Keenan DM, Takahashi PY, Liu PY, Roebuck PD, Nehra AX, Iranmanesh A, Veldhuis JD. Endocrinology 147: 2817-2828, 2006) was the highest (P = 0.019), and half-time to attain peak T concentrations was the shortest (P < 10(-6)), for 1-h rhLH pulses. Approximate entropy (a pattern-regularity measure) revealed more orderly T secretion for 1- than 2-h rhLH pulses (P = 0.0076). Accordingly, a pulsatile LH signal, while not obligatory to maintain mean T concentrations, controls the mean plasma LH concentration and determines quantifiable patterns of T secretion. These data introduce the question whether blood T patterns in turn supervise distinctive target-tissue responses.

Gender, Sex-Steroid, and Secretagogue-Selective Recovery from Growth Hormone-Induced Feedback in Older Women and Men

CONTEXT GH negatively regulates its own secretion. How gender, sex steroids, and secretagogues modulate GH autofeedback is not known. HYPOTHESIS/OBJECTIVE Supplementation with sex steroids and/or a peptidyl secretagogue will enhance the escape of GH from autoinhibition, thus framing a mechanism for amplifying pulsatile GH secretion. SUBJECTS AND SETTING Ten healthy postmenopausal women and 10 comparably aged men participated at the Clinical-Translational Science Unit. DESIGN/INTERVENTIONS Randomly ordered, double-blind, prospective crossover treatment with placebo vs. testosterone (men) or placebo vs. estradiol (women). Autofeedback was imposed by an iv pulse of GH. Recovery of feedback inhibition was quantified during constant infusion of saline, GHRH, or GH-releasing peptide-2 (three peptide categories). OUTCOMES/RESULTS During negative feedback, total (integrated) GH recovery depended upon gender (P = 0.017), sex hormone (P < 0.001), and peptide category (P < 0.001). Mechanistic analysis revealed that feedback-suppressed nadir GH concentrations were determined by sex-steroid treatment (P = 0.018) but not by gender (P = 0.444). Peak GH escape was controlled by both treatment (P = 0.004) and gender (P = 0.003). Nadir GH and peak GH during feedback were enhanced by GHRH or GHRP-2 (P < 0.001 for both). Gender × peptide (P = 0.012 for nadir GH), treatment × peptide (P < 0.001 total and peak GH), and gender × treatment (P = 0.017 nadir GH) regulated GH recovery interactively. CONCLUSION Gender, sex-steroid supplementation, and secretagogue type confer distinct feedback-rescuing effects, introducing a new level of complexity in the control of pulsatile GH regulation.

Short-Term Estradiol Supplementation Potentiates Low-Dose Ghrelin Action in the Presence of GHRH or Somatostatin in Older Women

CONTEXT Ghrelin is a potent gastric-derived GH-releasing peptide. How ghrelin interacts with sex steroids, GHRH, and somatostatin (SS) is not known. OBJECTIVE Our objective was to test the hypotheses that ghrelins interactions with GHRH (synergistic) and SS (disinhibitory) are ghrelin dose-dependent and amplified by estrogen. SUBJECTS, SETTING, AND DESIGN: Healthy postmenopausal women were treated with placebo (n=12) or 17β-estradiol (E2) (n=12) at the Center for Translational Science Activities in a randomized double-blind prospective study. METHODS Ghrelin dose-dependence was assessed by nonlinear curve fitting of the relationship between deconvolved GH secretory-burst mass and 5 randomly ordered ghrelin doses (0, 0.03, 0.135, 0.6, and 2.7 μg/kg bolus iv) during saline, GHRH, and SS infusion. RESULTS Under placebo, neither GHRH nor SS altered the ED50 of ghrelin (range 0.64-0.67 μg/kg). Under E2 (median E2 88 pg/mL), the ED50 of ghrelin declined in the presence of GHRH to 0.52 μg/kg. In contrast, the efficacy of ghrelin rose markedly during GHRH vs saline exposure with and without E2: placebo and saline 52±1.0 vs GHRH 173±3.8 μg/L; and E2 and saline 56±0.90 vs GHRH 174±3.7 μg/L. Sensitivity to ghrelin was similar under all conditions. SUMMARY Short-term E2 supplementation in postmenopausal women reduces the ED50 (increases the potency) of ghrelin when GHRH is present, without altering ghrelin efficacy (maximal effect) or hypothalamo-pituitary sensitivity (slope of dose response) to ghrelin. The data suggest possible physiological interactions among sex steroids (endogenous), ghrelin, and GHRH during E2 replacement in postmenopausal women.

Corticotropic axis drive of overnight cortisol secretion is suppressed in adolescents and young adults with type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is a pro‐inflammatory stress state, which, with its attendant hyperglycemia, likely disrupts hypothalamo‐pituitary‐adrenal (HPA) control, further dysregulating glucose homeostasis.

Multipathway Modulation of Exercise and Glucose Stress Effects upon GH Secretion in Healthy Men

OBJECTIVE Exercise evokes pulsatile GH release followed by autonegative feedback, whereas glucose suppresses GH release followed by rebound-like GH release (feedforward escape). Here we test the hypothesis that age, sex steroids, insulin, body composition and physical power jointly determine these dynamic GH responses. METHODS This was a prospectively randomized glucose-blinded study conducted in the Mayo Center for Advancing Translational Sciences in healthy men ages 19-77 years (N=23). Three conditions, fasting/rest/saline, fasting/exercise/saline and fasting/rest/iv glucose infusions, were used to drive GH dynamics during 10-min blood sampling for 6h. Linear correlation analysis was applied to relate peak/nadir GH dynamics to age, sex steroids, insulin, CT-estimated abdominal fat and physical power (work per unit time). RESULTS Compared with the fasting/rest/saline (control) day, fasting/exercise/saline infusion evoked peak GH within 1h, followed by negative feedback 3-5h later. The dynamic GH excursion was strongly (R(2)=0.634) influenced by (i) insulin negatively (P=0.011), (ii) power positively (P=0.0008), and (iii) E2 positively (P=0.001). Dynamic glucose-modulated GH release was determined by insulin negatively (P=0.0039) and power positively (P=0.0034) (R(2)=0.454). Under rest/saline, power (P=0.031) and total abdominal fat (P=0.012) (R(2)=0.267) were the dominant correlates of GH excursions. CONCLUSION In healthy men, dynamic GH perturbations induced by exercise and glucose are strongly related to physical power, insulin, estradiol, and body composition, thus suggesting a network of regulatory pathways.