Relationship between accessory renal arteries and resistant hypertension: A cohort study.

BACKGROUND: Resistant hypertension (RHT) is a major health care concern affecting 20 to 30% of hypertensive patients and increasing cardiovascular risk. Recent renal denervation trials have suggested a high prevalence of accessory renal arteries (ARA) in RHT. Our objective was to compare the prevalence of ARA in RHT vs. non-resistant hypertension (NRHT). METHODS: Eighty-six patients with essential hypertension who benefited from an abdominal CT-scan or MRI during their initial workup were retrospectively recruited in 6 French ESH (European Society of Hypertension) centers. At the end of a follow-up period of at least 6 months, patients were classified between RHT or NRHT. RHT was defined as uncontrolled blood pressure despite the optimal doses of three antihypertensive agents of which one is a diuretic or similar, or controlled by ≥ 4 medications. Blinded independent central review of all radiologic renal artery charts was performed. RESULTS: Baseline characteristics were: age 50±15 years, 62% males, BP 145±22/87±13mmHg. Fifty-three (62%) patients had RHT and 25 (29%) had at least one ARA. Prevalence of ARA was comparable between RHT (25%) and NRHT patients (33%, P=0.62), but there were more ARA per patient in NRHT (2±0.9) vs. RHT (1.3±0.5, P=0.05), and renin levels were higher in ARA group (51.6±41.7 mUI/L vs. 20.4±25.4 mUI/L, P=0.001). ARA were similar in diameter or length between the 2 groups. CONCLUSIONS: In this retrospective series of 86 essential hypertension patients, we found no difference in the prevalence of ARA in RHT and NRHT. More comprehensive studies are needed to answer this question.

Discovery of a novel series of potent S1P1 agonists.

The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.

A cellular assay for measuring the inhibition of glycogen synthase kinase-3 via the accumulation of beta-catenin in Chinese hamster ovary clone K1 cells.

Glycogen synthase kinase-3 (GSK3) is a serine-threonine protein kinase that exists as two isozymes, GSK3alpha and GSK3beta. It plays important roles in regulating cell structure, function, and survival, and dysregulation of its function is linked to disorders such as Alzheimer's disease and type II diabetes. In resting cells, GSK3 is active and regulates the function of many downstream targets, including beta-catenin. We describe the development of a cell-based assay designed to measure the activity of GSK3 by directly measuring the accumulation of beta-catenin in Chinese hamster ovary clone K1 (CHOK1) cells. Beta-catenin levels were assessed using an antibody-based staining protocol with a luminometric readout. The assay is set up in a 96-well format. The use of GSK3 inhibitors demonstrated that this assay could be used to compare the effects of various small molecules on GSK3 inhibition in CHOK1 cells.

Arteries, inflammation and insulin resistance.

Inflammation plays a role in all stages of atherosclerosis from the formation to the rupture of the plaque. Guided by inflammatory mediators, monocytes bind to an endothelium damaged by cardiovascular risk factors, and then migrate towards the intima where, after incorporating oxidized low-density lipoprotein particles, they are transformed into foam cells. The lipid streak forms and develops as an atherosclerotic plaque, which is susceptible to erosion and rupture. Inflammation fed by excess adipose tissue decreases insulin sensitivity, which is the central feature of the metabolic syndrome. Inflammation therefore appears to be a common factor of atherosclerosis and the metabolic syndrome. The factors triggering this inflammation have yet to be determined. One line of thought would appear to point to diet.

Pharmacophore-based design of novel oxadiazoles as selective sphingosine-1-phosphate (S1P) receptor agonists with in vivo efficacy.

Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure-activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five-membered heterocycles, and the use of diverse 2,2'-disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N-methyl-N-(4-{5-[2-methyl-2'-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (45), and a dual S1P1,5 agonist, N-methyl-N-(3-{5-[2'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (49), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head-to-head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan-S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1 -selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.

Aldosterone-to-renin ratio for diagnosing aldosterone-producing adenoma: a multicentre study.

BACKGROUND: Biological diagnostic criteria for diagnosing aldosterone-producing adenoma (APA) are not well-established. AIM: The aim of the study was to establish the best biological predictors of APA. METHODS: A prospective register was implemented in 17 secondary or tertiary hypertension centres. The inclusion criterion was one of the following: onset of hypertension before 40 years of age; history of hypokalaemia; drug-resistant hypertension (resistant to three drugs); or spironolactone efficiency on BP. RESULTS: Among the 338 collected cases, 192 patients had two aldosterone-to-renin ratio (ARR) determinations (after 1 hour supine and at least 1 hour upright) on the same occasion. Twenty-five patients (8.2%) had biological hyperaldosteronism and an adrenal adenoma identified by computed tomography. APA was histologically confirmed in all 12 patients who underwent surgery. Histologically proven APAs were used as the 'gold standard' in receiver operating characteristic (ROC) curve analysis. ARRs were computed with a minimum renin value set at 5 ng/L to avoid misclassification of so-called 'low-renin hypertension'. To predict an APA, the ARR area under the ROC curve was 0.93. A supine ARR cut-off value of 32ng/ng provided the highest sum of sensitivity (92%) plus specificity (92%). On the basis of an ARR≥32 ng/ng in the supine and/or upright position, sensitivity reached 100%. CONCLUSION: The proposed cut-off value of 32 ng/ng for ARR (minimum renin value set at 5 ng/L) in one of two determinations had 100% sensitivity and 72% specificity with 20% positive and 100% negative predictive values for diagnosing APA.

PPARγ ligands switched high fat diet-induced macrophage M2b polarization toward M2a thereby improving intestinal Candida elimination.

Obesity is associated with a chronic low-grade inflammation that predisposes to insulin resistance and the development of type 2 diabetes. In this metabolic context, gastrointestinal (GI) candidiasis is common. We recently demonstrated that the PPARγ ligand rosiglitazone promotes the clearance of Candida albicans through the activation of alternative M2 macrophage polarization. Here, we evaluated the impact of high fat diet (HFD)-induced obesity and the effect of rosiglitazone (PPARγ ligand) or WY14643 (PPARα ligand) both on the phenotypic M1/M2 polarization of peritoneal and cecal tissue macrophages and on the outcome of GI candidiasis. We demonstrated that the peritoneal macrophages and the cell types present in the cecal tissue from HF fed mice present a M2b polarization (TNF-α(high), IL-10(high), MR, Dectin-1). Interestingly, rosiglitazone induces a phenotypic M2b-to-M2a (TNF-α(low), IL-10(low), MR(high), Dectin-1(high)) switch of peritoneal macrophages and of the cells present in the cecal tissue. The incapacity of WY14643 to switch this polarization toward M2a state, strongly suggests the specific involvement of PPARγ in this mechanism. We showed that in insulin resistant mice, M2b polarization of macrophages present on the site of infection is associated with an increased susceptibility to GI candidiasis, whereas M2a polarization after rosiglitazone treatment favours the GI fungal elimination independently of reduced blood glucose. In conclusion, our data demonstrate a dual benefit of PPARγ ligands because they promote mucosal defence mechanisms against GI candidiasis through M2a macrophage polarization while regulating blood glucose level.

Improvement of Young and Elderly Patient's Knowledge of Heart Failure After an Educational Session.

BACKGROUND: Interest in the role of patient education sessions for optimizing the management of heart failure (HF) is increasing. We determined whether improvements in young and elderly patients' knowledge of HF and self-care behavior could be analyzed by administering a knowledge test before and after an educational session. METHODS: Stable heart failure patients (n = 115) were enrolled in a prospective cohort study from our Heart Failure educational centre in a university hospital. Patient knowledge of six major HF-related topics was assessed via a questionnaire distributed once before an educational session and twice afterward. Each answer was assigned a numerical value and the final score for each topic could range from 0 to 20. Scores >/= 15/20 were considered representative of a good level of knowledge. RESULTS: The level of knowledge was low (9.7/20) before the educational session but was significantly higher (16.3/20) during the 1st quarter after the session, and this benefit was maintained for up to 12 months (16.6/20). Knowledge levels increased in both younger and elderly patients, and the number of patients who had a good level of knowledge also increased after the educational session. CONCLUSION: This study confirms that an HF knowledge test is feasible and that educational sessions improve the knowledge and self-management of both younger and elderly patients.