Adipocytes, aldosterone and obesity-related hypertension

Understanding the mechanisms linking obesity with hypertension is important in the current obesity epidemic as it may improve therapeutic interventions. Plasma aldosterone levels are positively correlated with body mass index and weight loss in obese patients is reported to be accompanied by decreased aldosterone levels. This suggests a relationship between adipose tissue and the production/secretion of aldosterone. Aldosterone is synthesized principally by the adrenal glands, but its production may be regulated by many factors, including factors secreted by adipocytes. In addition, studies have reported local synthesis of aldosterone in extra-adrenal tissues, including adipose tissue. Experimental studies have highlighted a role for adipocyte-secreted aldosterone in the pathogenesis of obesity-related cardiovascular complications via the mineralocorticoid receptor. This review focuses on how aldosterone secretion may be influenced by adipose tissue and the importance of these mechanisms in the context of obesity-related hypertension

The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1 pulmonary circulation

Pulmonary arterial hypertension (PAH) is a devastating vasculopathy that predominates in women and has been associated with dysregulated estrogen and serotonin signaling. Overexpression of the serotonin transporter (SERT+) in mice results in an estrogen-dependent development of pulmonary hypertension (PH). Estrogen metabolism by cytochrome P450 1B1 (CYP1B1) contributes to the pathogenesis of PAH, and serotonin can increase CYP1B1 expression in human pulmonary arterial smooth muscle cells (hPASMCs). We hypothesized that an increase in intracellular serotonin via increased SERT expression may dysregulate estrogen metabolism via CYP1B1 to facilitate PAH. Consistent with this hypothesis, we found elevated lung CYP1B1 protein expression in female SERT+ mice accompanied by PH, which was attenuated by the CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS). Lungs from female SERT+ mice demonstrated an increase in oxidative stress that was marked by the expression of 8-hydroxyguanosine; however, this was unaffected by CYP1B1 inhibition. SERT expression was increased in monocrotaline-induced PH in female rats; however, TMS did not reverse PH in monocrotaline-treated rats but prolonged survival. Stimulation of hPASMCs with the CYP1B1 metabolite 16α-hydroxyestrone increased cellular proliferation, which was attenuated by an inhibitor (MPP) of estrogen receptor alpha (ERα) and a specific ERα antibody. Thus, increased intracellular serotonin caused by increased SERT expression may contribute to PAH pathobiology by dysregulation of estrogen metabolic pathways via increased CYP1B1 activity. This promotes PASMC proliferation by the formation of pathogenic metabolites of estrogen that mediate their effects via ERα. Our studies indicate that targeting this pathway in PAH may provide a promising antiproliferative therapeutic strategy

High fat diet attenuates the anticontractile activity of aortic PVAT via a mechanism involving AMPK and reduced adiponectin secretion

Background and aim: Perivascular adipose tissue (PVAT) positively regulates vascular function through production of factors such as adiponectin but this effect is attenuated in obesity. The enzyme AMP-activated protein kinase (AMPK) is present in PVAT and is implicated in mediating the vascular effects of adiponectin. In this study, we investigated the effect of an obesogenic high fat diet (HFD) on aortic PVAT and whether any changes involved AMPK. Methods: Wild type Sv129 (WT) and AMPKα1 knockout (KO) mice aged 8 weeks were fed normal diet (ND) or HFD (42% kcal fat) for 12 weeks. Adiponectin production by PVAT was assessed by ELISA and AMPK expression studied using immunoblotting. Macrophages in PVAT were identified using immunohistochemistry and markers of M1 and M2 macrophage subtypes evaluated using real time-qPCR. Vascular responses were measured in endothelium-denuded aortic rings with or without attached PVAT. Carotid wire injury was performed and PVAT inflammation studied 7 days later. Key results: Aortic PVAT from KO and WT mice was morphologically indistinct but KO PVAT had more infiltrating macrophages. HFD caused an increased infiltration of macrophages in WT mice with increased expression of the M1 macrophage markers Nos2 and Il1b and the M2 marker Chil3. In WT mice, HFD reduced the anticontractile effect of PVAT as well as reducing adiponectin secretion and AMPK phosphorylation. PVAT from KO mice on ND had significantly reduced adiponectin secretion and no anticontractile effect and feeding HFD did not alter this. Wire injury induced macrophage infiltration of PVAT but did not cause further infiltration in KO mice. Conclusions: High-fat diet causes an inflammatory infiltrate, reduced AMPK phosphorylation and attenuates the anticontractile effect of murine aortic PVAT. Mice lacking AMPKα1 phenocopy many of the changes in wild-type aortic PVAT after HFD, suggesting that AMPK may protect the vessel against deleterious changes in response to HFD

HIV proteinase inhibitors target the Ddi1-like protein of Leishmania parasites

HIV proteinase inhibitors reduce the levels of Leishmania parasites in vivo and in vitro, but their biochemical target is unknown. We have identified an ortholog of the yeast Ddi1 protein as the only member of the aspartic proteinase family in Leishmania parasites, and in this study we investigate this protein as a potential target for the drugs. To date, no enzyme assay has been developed for the Ddi1 proteins, but Saccharomyces cerevisiae lacking the DDI1 gene secrete high levels of protein into the medium. We developed an assay in which these knockout yeast were functionally complemented to low secretion by introduction of genes encoding Ddi1 orthologs from Leishmania major or humans. Plasmid alone controls gave no complementation. Treatment of the Ddi1 transformants with HIV proteinase inhibitors showed differential effects dependent on the origin of the Ddi1. Dose responses allowed calculation of IC50 values; e.g., for nelfinavir, of 3.4 μM (human Ddi1) and 0.44 μM (Leishmania Ddi1). IC50 values with Leishmania constructs mirror the potency of inhibitors against parasites. Our results show that Ddi1 proteins are targets of HIV proteinase inhibitors and indicates the Leishmania Ddi1 as the likely target for these drugs and a potential target for antiparasitic therapy

Diffusion of effects of the ASSIST school‐based smoking prevention intervention to non‐participating family members: a secondary analysis of a randomized controlled trial

Aims: To investigate whether effects of the ASSIST (A Stop Smoking In Schools Trial) school‐based smoking prevention intervention diffused from students to the people they lived with. Design: Secondary analysis of a cluster‐randomized control trial (cRCT). Setting: England and Wales. Participants: A total of 10 730 students aged 12–13 years in 59 schools assigned using stratified block randomization to the control (29 schools, 5372 students) or intervention (30 schools, 5358 students) condition. Intervention and comparator: The ASSIST intervention involves 2 days of off‐site training of influential students to encourage their peers not to smoke during a 10‐week period. The control group continued with their usual education. Measurements: The outcomes were the proportion of students who self‐reported living with a smoker and the smoking status of each resident family member/caregiver. Follow‐up assessments were immediately after the intervention and at 1 and 2 years post‐intervention. Findings: The odds ratio (OR) for living with a smoker in the intervention compared with the control groups was 0.86 [95% confidence interval (CI) = 0.72, 1.03] immediately after the intervention, OR = 0.84 (95% CI = 0.72, 0.97) at a 1‐year follow‐up and OR = 0.86 (95% CI = 0.75, 0.99) at 2‐year follow‐up. In a three‐tier multi‐level model with data from all three follow‐ups, student‐reported smoking by fathers (OR = 0.90, 95% CI = 0.80, 1.00), brothers (OR = 0.78, 95% CI = 0.67, 0.92) and sisters (OR = 0.80, 95% CI = 0.69, 0.92) was lower in the intervention compared with control group. Subgroup analyses by baseline smoking status suggested that these effects were more consistent with prevention of uptake than prompting cessation. Conclusions: A Stop Smoking In Schools Trial (ASSIST) school‐based smoking prevention intervention may have reduced the prevalence of smoking in people who lived with ASSIST‐trained students. This indirect transmission is consistent with the predictions of diffusion of innovations theory which underpins the design of ASSIST

A Randomised Phase 2 Trial of Intensive Induction Chemotherapy (CBOP/BEP) and Standard BEP in Poor-prognosis Germ Cell Tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604)

AbstractBackgroundStandard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required.ObjectiveTo explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial.Design, setting, and participantsWe conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres.InterventionBEP (bleomycin 30 000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15 000 IU).Outcome measurements and statistical analysisPrimary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates.Results and limitationsA total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61–85) with CBOP/BEP, 61% with BEP (90% CI, 48–73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33–1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS.ConclusionsThe primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial.Patient summaryIn this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration.Trial registrationISRCTN53643604; http://www.controlled-trials.com/ISRCTN53643604

Reply: Cisplatin-associated aortic thrombosis: a review of cases reported to the FDA adverse event reporting system

No abstract available

Comprehensive characterisation of the vascular effects of cisplatin-based chemotherapy in patients with testicular cancer

Background: Cisplatin-based chemotherapy increases the risk of cardiovascular and renal disease. Objectives: We aimed to define the time course, pathophysiology, and approaches to prevent cardiovascular disease associated with cisplatin-based chemotherapy. Methods: Two cohorts of patients with a history of testicular cancer (n = 53) were recruited. Cohort 1 consisted of 27 men undergoing treatment with: 1) surveillance; 2) 1 to 2 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy (low-intensity cisplatin); or 3) 3 to 4 cycles of BEP (high-intensity cisplatin). Endothelial function (percentage flow-mediated dilatation) and cardiovascular biomarkers were assessed at 6 visits over 9 months. Cohort 2 consisted of 26 men previously treated 1 to 7 years ago with surveillance or 3 to 4 cycles BEP. Vasomotor and fibrinolytic responses to bradykinin, acetylcholine, and sodium nitroprusside were evaluated using forearm venous occlusion plethysmography. Results: In cohort 1, the percentage flow-mediated dilatation decreased 24 h after the first cisplatin dose in patients managed with 3 to 4 cycles BEP (10.9 ± 0.9 vs. 16.7 ± 1.6; p &lt; 0.01) but was unchanged from baseline thereafter. Six weeks after starting 3 to 4 cycles BEP, there were increased serum cholesterol levels (7.2 ± 0.5 mmol/l vs. 5.5 ± 0.2 mmol/l; p = 0.01), hemoglobin A1c (41.8 ± 2.0 mmol/l vs. 35.5 ± 1.2 mmol/l; p &lt; 0.001), von Willebrand factor antigen (62.4 ± 5.4 mmol/l vs. 45.2 ± 2.8 mmol/l; p = 0.048) and cystatin C (0.91 ± 0.07 mmol/l vs. 0.65 ± 0.09 mmol/l; p &lt; 0.01). In cohort 2, intra-arterial bradykinin, acetylcholine, and sodium nitroprusside caused dose-dependent vasodilation (p &lt; 0.0001). Vasomotor responses, endogenous fibrinolytic factor release, and cardiovascular biomarkers were not different in patients managed with 3 to 4 cycles of BEP versus surveillance. Conclusions: Cisplatin-based chemotherapy induces acute and transient endothelial dysfunction, dyslipidemia, hyperglycemia, and nephrotoxicity in the early phases of treatment. Cardiovascular and renal protective strategies should target the early perichemotherapy period. (Clinical Characterisation of the Vascular Effects of Cis-platinum Based Chemotherapy in Patients With Testicular Cancer [VECTOR], NCT03557177; Intermediate and Long Term Vascular Effects of Cisplatin in Patients With Testicular Cancer [INTELLECT], NCT03557164

The contribution of geology and groundwater studies to city-scale ground source heat network strategies: a case study from Cardiff, Wales, UK

The development of integrated heat network strategies involving exploitation of the shallow subsurface requires knowledge of ground conditions at the feasibility stage, and throughout the life of the system. We describe an approach to the assessment of ground constraints and energy opportunities in data-rich urban areas. Geological and hydrogeological investigations have formed a core component of the strategy development for sustainable thermal use of the subsurface in Cardiff, UK. We present findings from a 12 month project titled ‘Ground Heat Network at a City Scale’, which was co-funded by NERC/BGS and the UK Government through the InnovateUK Energy Catalyst grant in 2015-16. The project examined the technical feasibility of extracting low grade waste heat from a shallow gravel aquifer using a cluster of open loop ground source heat pumps. Heat demand mapping was carried out separately. The ground condition assessment approach involved the following steps: (1) city-wide baseline groundwater temperature mapping in 2014 with seasonal monitoring for at least 12 months prior to heat pump installation (Patton et al 2015); (2) desk top and field-based investigation of the aquifer system to determine groundwater levels, likely flow directions, sustainable pumping yields, water chemistry, and boundary conditions; (3) creation of a 3D geological framework model with physical property testing and model attribution; (4) use steps 1-3 to develop conceptual ground models and production of maps and GIS data layers to support scenario planning, and initial heat network concept designs; (5) heat flow modelling in FEFLOW software to analyse sustainability and predict potential thermal breakthrough in higher risk areas; (6) installation of a shallow open loop GSHP research observatory with real-time monitoring of groundwater bodies to provide data for heat flow model validation and feedback for system control. In conclusion, early ground condition modelling and subsurface monitoring have provided an initial indication of ground constraints and opportunities supporting development of aquifer thermal energy systems in Cardiff. Ground models should consider the past and future anthropogenic processes that influence and modify the condition of the ground. These include heat losses from buildings, modification of the groundwater regime by artificial pumping, sewers, and other GSH schemes, and construction hazards such as buried infrastructure, old foundations, land contamination and un-exploded ordnance. This knowledge base forms the foundation for a ‘whole life’ approach for sustainable thermal use of the subsurface. Benefits of the approach include; timely and easy to understand information for land use and financial resource planning, reduced financial risk for developers and investors, clear evidence to help improve public perception of GSHP technology, and provision of independent environmental data to satisfy the needs of the regulator