Hypothalamic Response to Kisspeptin-54 and Pituitary Response to Gonadotropin-Releasing Hormone Are Preserved in Healthy Older Men.

BACKGROUND: Male testosterone levels decline by 1% per year from the age of 40 years. Whilst a primary testicular deficit occurs, hypothalamic or pituitary dysregulation may also coexist. This study aimed to compare the hypothalamic response to kisspeptin-54 and the pituitary response to gonadotropin-releasing hormone (GnRH) of older men with those of young men. METHODS: Following 1 h of baseline sampling, healthy older men (n = 5, mean age 59.3 ± 2.9 years) received a 3-h intravenous infusion of either vehicle, kisspeptin-54 0.1, 0.3, or 1.0 nmol/kg/h or GnRH 0.1 nmol/kg/h, on five different study days. Serum gonadotropins and total testosterone were measured every 10 min and compared to those of young men (n = 5/group) (mean age 28.9 ± 2.0 years) with a similar body mass index (24 kg/m2) who underwent the same protocol. RESULTS: Kisspeptin-54 and GnRH significantly stimulated serum gonadotropin release in older men compared to vehicle (p < 0.001 for all groups). Gonadotropin response to kisspeptin-54 was at least preserved in older men when compared to young men. At the highest dose of kisspeptin-54 (1.0 nmol/kg/h), a significantly greater luteinising hormone (LH) (p = 0.003) response was observed in older men. The follicle-stimulating hormone (FSH) response to GnRH was increased in older men (p = 0.002), but the LH response was similar (p = 0.38). Serum testosterone rises following all doses of kisspeptin-54 (p ≤ 0.009) were reduced in older men. CONCLUSIONS: Our data suggest that healthy older men without late-onset hypo-gonadism (LOH) have preserved hypothalamic response to kisspeptin-54 and pituitary response to GnRH, but impaired testicular response. Further work is required to investigate the use of kisspeptin-54 to identify hypothalamic deficits in men with LOH.

Side-specific endothelial-dependent regulation of aortic valve calcification: interplay of hemodynamics and nitric oxide signaling.

Arterial endothelial cells maintain vascular homeostasis and vessel tone in part through the secretion of nitric oxide (NO). In this study, we determined how aortic valve endothelial cells (VEC) regulate aortic valve interstitial cell (VIC) phenotype and matrix calcification through NO. Using an anchored in vitro collagen hydrogel culture system, we demonstrate that three-dimensionally cultured porcine VIC do not calcify in osteogenic medium unless under mechanical stress. Co-culture with porcine VEC, however, significantly attenuated VIC calcification through inhibition of myofibroblastic activation, osteogenic differentiation, and calcium deposition. Incubation with the NO donor DETA-NO inhibited VIC osteogenic differentiation and matrix calcification, whereas incubation with the NO blocker l-NAME augmented calcification even in 3D VIC-VEC co-culture. Aortic VEC, but not VIC, expressed endothelial NO synthase (eNOS) in both porcine and human valves, which was reduced in osteogenic medium. eNOS expression was reduced in calcified human aortic valves in a side-specific manner. Porcine leaflets exposed to the soluble guanylyl cyclase inhibitor ODQ increased osteocalcin and α-smooth muscle actin expression. Finally, side-specific shear stress applied to porcine aortic valve leaflet endothelial surfaces increased cGMP production in VEC. Valve endothelial-derived NO is a natural inhibitor of the early phases of valve calcification and therefore may be an important regulator of valve homeostasis and pathology.

Long-term outcomes after autograft versus homograft aortic root replacement in adults with aortic valve disease: a randomised controlled trial.

BACKGROUND: The ideal substitute for aortic valve replacement in patients with aortic valve disease is not known. Our hypothesis was that the regulatory and adaptive properties of a living valve substitute could improve the long-term outcomes in patients. We therefore compared these outcomes after autograft aortic root replacement (Ross procedure) versus homograft aortic root replacement in adults. METHODS: Male and female patients (<69 years) requiring aortic valve surgery were randomly assigned in a one-to-one ratio to receive an autograft or a homograft aortic root replacement in one centre in the UK. The random allocation sequence was computer generated. Treatment was not masked. The primary endpoint was survival of patients at 10 years after surgery. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN03530985. FINDINGS: 228 patients were randomly assigned to receive an autograft or a homograft aortic root replacement. 12 patients were excluded because they were younger than 18 years; 108 in each group received the surgery they were assigned to and were analysed. There was one (<1%) perioperative death in the autograft group versus three (3%) in the homograft group (p=0.621). At 10 years, four patients died in the autograft group versus 15 in the homograft group. Actuarial survival at 10 years was 97% (SD 2) in the autograft group versus 83% (4) in the homograft group. Hazard ratio for death in the homograft group was 4.61 (95% CI 1.71-16.03; p=0.0060). Survival of patients in the autograft group was similar to that in an age-matched and sex-matched British population (96%). INTERPRETATION: Our findings support the hypothesis that a living valve implanted in the aortic position can significantly improve the long-term outcomes in patients. FUNDING: Funding Magdi Yacoub Institute.

Extended Recipient Criteria in Lung Transplantation: Impact of Pleural Abnormalities on Primary Graft Dysfunction.

BACKGROUND: Because of improved surgical expertise and intraoperative management, pleural disease (PD+) represents a relatively minor contraindication to lung transplantation (LTx). The presence of pleural abnormalities from previous procedures or pleural involvement from fungal or bacterial disease is not considered a limiting factor for LTx. However there are no studies available to assess the impact of pleural diseases on short- and midterm outcomes after LTx. METHODS: We retrospectively reviewed 163 consecutive patients who underwent LTx between 2010 and 2013. Patients were divided according to the presence of pleural abnormalities before the operation (PD+ versus PD-). The primary end point of the study was primary graft dysfunction (PGD; grade 3) and overall survival. To avoid possible selection bias and to heck the robustness of the results, a propensity score-matching analysis (1:3) was performed. RESULTS: A total of 26 patients (16%) had pleural abnormalities before transplantation. Intra- and postoperative variables were comparable. PD+ was associated with a significantly higher incidence of PGD at 0 and 48 hours postoperatively (p = 0.037 and p = 0.032, respectively). Moreover, PD+ was associated with significantly worse survival at 3 months (p = 0.021). Although there was a trend toward worse early overall survival in the Kaplan-Meier estimate (Breslow p = 0.050), midterm survival was comparable (log-rank p = 0.240). CONCLUSIONS: LTx in patients with preoperative pleural abnormalities is feasible. Identifying higher-risk recipients with pleural abnormalities might have important clinical relevance because of a higher incidence of PGD and worse early survival, even though midterm survival is comparable.

Neurokinin B administration induces hot flushes in women.

Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms), and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers.

Endoscopic vein harvesting: technique, outcomes, concerns & controversies.

The choice of the graft conduit for coronary artery bypass grafting (CABG) has significant implications both in the short- and long-term. The patency of a coronary conduit is closely associated with an uneventful postoperative course, better long-term patient survival and superior freedom from re-intervention. The internal mammary artery is regarded as the primary conduit for CABG patients, given its association with long-term patency and survival. However, long saphenous vein (LSV) continues to be utilized universally as patients presenting for CABG often have multiple coronary territories requiring revascularization. Traditionally, the LSV has been harvested by creating incisions from the ankle up to the groin termed open vein harvesting (OVH). However, such harvesting methods are associated with incisional pain and leg wound infections. In addition, patients find such large incisions to be cosmetically unappealing. These concerns regarding wound morbidity and patient satisfaction led to the emergence of endoscopic vein harvesting (EVH). Published experience comparing OVH with EVH suggests decreased wound related complications, improved patient satisfaction, shorter hospital stay, and reduced postoperative pain at the harvest site following EVH. Despite these reported advantages concerns regarding risk of injury at the time of harvest with its potential detrimental effect on vein graft patency and clinical outcomes have prevented universal adoption of EVH. This review article provides a detailed insight into the technical aspects, outcomes, concerns, and controversies associated with EVH.

Late outcomes following freestyle versus homograft aortic root replacement: results from a prospective randomized trial.

OBJECTIVES: The aims of this study were to compare long-term results after homograft versus Freestyle (Medtronic Inc., Minneapolis, Minnesota) aortic root replacement. BACKGROUND: The ideal substitute for aortic root replacement remains undetermined. METHODS: Between 1997 and 2005, 166 patients (age 65 +/- 8 years) undergoing total aortic root replacement were randomized to receive a homograft (n = 76) or a Freestyle bioprosthesis (n = 90). Six patients randomly assigned to homograft crossed over to Freestyle because of unavailability of suitably sized homografts. Median follow-up was 7.6 years (maximum 11 years; 1,035 patient-years). "Evolving" aortic valve dysfunction was defined as aortic regurgitation >/=2/4 and/or peak gradient >20 mm Hg. RESULTS: Patient characteristics were comparable between groups. Concomitant procedures were performed in 44% and 47% of Freestyle and homograft patients, respectively (p = 0.5). Overall hospital mortality was 4.8% (1% for isolated root replacement). Eight-year survival was 80 +/- 5% in the Freestyle group versus 77 +/- 6% in the homograft group (p = 0.9). Freedom from need for reoperation at 8 years was significantly higher after Freestyle root replacement (100 +/- 0% vs. 90 +/- 5% after homograft replacement; p = 0.02). All reoperations were secondary to structural valve deterioration (n = 6). At last echocardiographic follow-up, actuarial freedom from evolving aortic valve dysfunction was 86 +/- 5% for Freestyle bioprostheses versus 37 +/- 7% for homografts (p < 0.001). Clinically, freedom from New York Heart Association functional class III to IV and freedom from valve-related complications were similar between groups (p = 0.7 and p = 0.9, respectively). CONCLUSIONS: In this patient group, late survival is similar after homograft versus Freestyle root replacement. However, Freestyle aortic root replacement is associated with significantly less progressive aortic valve dysfunction and a lower need for reoperations.