0272: True antihypertensive efficacy of sequential nephron blockade in patients with resistant hypertension and confirmed medication adherence

ObjectiveWe previously showed (Bobrie et al. J Hypertens 2012) that sequential-nephron blockade (SNB) was more effective than combined renin angiotensin system blockade (RB) for controlling BP in patients with resistant hypertension (RH). In this post-hoc analysis, we assessed medication adherence (MA) and its influence on the antihypertensive response to SNB/RB with a new combined scoring system.Design and MethodPts with daytime ambulatory SBP/DBP (dASBP/dADBP) >135 and/or 85mmHg, despite 4 week-treatment with irbesartan 300mg+HCTZ 12.5mg+amlodipine 5mg, were randomised either to SNB (i.e.+spironolactone 25mg, then +furosemide 20-40mg, then +amiloride 5mg, n=82) or RB (ramipril 5-10mg, then bisoprolol 5-10mg, RB group, n=82) for 12 weeks. MA was scored according to 4 criteria: (i) trough/peak plasma irbesartan (Irb) concentration (HPLC); (ii) urinary AcSDKP/creatinine ratio (UR) to evaluate ramipril intake; (iii) delay of last medication intake before visit (LMI); and (iv) pill counting (PC, %). One point of MA score was attributed to trough Irb >20ng/ml, UR >4nmol/mmol, LMI <24h and PC >80%. MA was defined as low (LMA, score <2), intermediate (IMA, score=3), and optimal (OMA, score=4).Results82 pts among 164 had OMA (46 SNB and 36 RB); 52 pts had IMA (23 SNB and 29 RB); and 30 pts had LMA (13 SNB and 17 RB) (inter-groups difference: NS). LMA pts were younger than SMA pts (50±11 vs. 56±10 yrs, p<0.011). In OMA pts, the difference in dASBP/dADBP between SNB vs RB was significant (–11 [–17;–6]/–6 [–9;–2] mmHg, p<0.0001/p=0.0025), favoring SNB, whereas in LMA pts the significant difference between the two groups was no more observed (–6 [–19;7]/–1 [–10;7] mmHg, p=0.352/p=0.7096).ConclusionThe major BP lowering effect of SNB vs. RB observed in pts with OMA is lost in pts LMA. Combined methods for assessing MA allow determining the true efficacy of antihypertensive strategies in patients with RH. Reinforcement of MA in RH pts is deemed necessary

Calcium-dependent mitochondrial cAMP production enhances aldosterone secretion

Glomerulosa cells secrete aldosterone in response to agonists coupled to Ca2+ increases such as angiotensin II and corticotrophin, coupled to a cAMP dependent pathway. A recently recognized interaction between Ca2+ and cAMP is the Ca2+-induced cAMP formation in the mitochondrial matrix. Here we describe that soluble adenylyl cyclase (sAC) is expressed in H295R adrenocortical cells. Mitochondrial cAMP formation, monitored with a mitochondria-targeted fluorescent sensor (4mtH30), is enhanced by HCO3 - and the Ca2+ mobilizing agonist angiotensin II. The effect of angiotensin II is inhibited by 2-OHE, an inhibitor of sAC, and by RNA interference of sAC, but enhanced by an inhibitor of phosphodiesterase PDE2A. Heterologous expression of the Ca2+ binding protein S100G within the mitochondrial matrix attenuates angiotensin II-induced mitochondrial cAMP formation. Inhibition and knockdown of sAC significantly reduce angiotensin II-induced aldosterone production. These data provide the first evidence for a cell-specific functional role of mitochondrial cAMP. © 2015 Elsevier Ireland Ltd

2009 Pandemic Influenza A (H1N1) Virus Outbreak and Response – Rwanda, October, 2009–May, 2010

BACKGROUND: In October 2009, the first case of pandemic influenza A(H1N1)pdm09 (pH1N1) was confirmed in Kigali, Rwanda and countrywide dissemination occurred within several weeks. We describe clinical and epidemiological characteristics of this epidemic. METHODS: From October 2009 through May 2010, we undertook epidemiologic investigations and response to pH1N1. Respiratory specimens were collected from all patients meeting the WHO case definition for pH1N1, which were tested using CDC's real time RT-PCR protocol at the Rwandan National Reference Laboratory (NRL). Following documented viral transmission in the community, testing focused on clinically severe and high-risk group suspect cases. RESULTS: From October 9, 2009 through May 31, 2010, NRL tested 2,045 specimens. In total, 26% (n = 532) of specimens tested influenza positive; of these 96% (n = 510) were influenza A and 4% (n = 22) were influenza B. Of cases testing influenza A positive, 96.8% (n = 494), 3% (n = 15), and 0.2% (n = 1) were A(H1N1)pdm09, Seasonal A(H3) and Seasonal A(non-subtyped), respectively. Among laboratory-confirmed cases, 263 (53.2%) were children <15 years and 275 (52%) were female. In total, 58 (12%) cases were hospitalized with mean duration of hospitalization of 5 days (Range: 2-15 days). All cases recovered and there were no deaths. Overall, 339 (68%) confirmed cases received oseltamivir in any setting. Among all positive cases, 26.9% (143/532) were among groups known to be at high risk of influenza-associated complications, including age <5 years 23% (122/532), asthma 0.8% (4/532), cardiac disease 1.5% (8/532), pregnancy 0.6% (3/532), diabetes mellitus 0.4% (2/532), and chronic malnutrition 0.8% (4/532). CONCLUSIONS: Rwanda experienced a PH1N1 outbreak which was epidemiologically similar to PH1N1 outbreaks in the region. Unlike seasonal influenza, children <15 years were the most affected by pH1N1. Lessons learned from the outbreak response included the need to strengthen integrated disease surveillance, develop laboratory contingency plans, and evaluate the influenza sentinel surveillance system

Perte rénale de Sodium et de Potassium chez les patients de syndrome de DENT (Evolution avec la progression de l'insuffisance rénale)

Le syndrome de DENT est une maladie récessive liée au chromosome X secondaire à une mutation du gène du canal chlore CLC-5, exprimé majoritairement dans le tubule proximal mais aussi dans la branche ascendante large et le canal collecteur. Le phénotype associe une protéinurie de bas poids moléculaire, une hypercalciurie généralement compliquée de néphrocalcinose et/ou lithiase.L'hypokaliémie déjà décrite et retrouvée chez nos patients est mal comprise.Objectifs : 1) réaliser une étude phénotypique pour démontrer l'évolutivité de la symptomatologie avec l'âge, 2) documenter l'existence de la perte rénale de sodium chez les adultes pouvant expliquer l'hypokaliémie observée et la rechercher chez les enfants. Méthodes : les données cliniques et génétiques de 24 patients ont été rétrospectivement analysées. La recherche d'une perte rénale de NaCl a pu être réalisée chez 4 adultes et 1 enfant. Une épreuve de charge en NaCl hypotonique a été réalisée chez un patient. Résultats : L'étude phénotypique des 18 patients ayant une mutation de CLC-5 montrait avant l'âge de 15 ans, un tableau classique, sans insuffisance rénale. Le débit de filtration glomérulaire baissait régulièrement avec l'âge (2.3mL/min/1.73 m2/an). À l'âge adulte, ces patients avaient une insuffisance rénale évoluée et paradoxalement, une hypokaliémie d'origine rénale. Les 4 patients adultes (34 +ou-8 ans) étudiée en détail, présentaient une insuffisance rénale (DFG 54 +ou-0.6 mL/min/1.73 m carré), un tableau d'hyperaldostéronisme secondaire (Aldo 998 +ou-674 pmol/L, Rénine 735 +ou- 1148 pg/mL) et une natriurèse conservée (162 mmol/24h00) démontrant l'existence dune perte rénale de NaCl. Chez un patient, la réabsorption sodée dans le segment de dilution était normale. L'enfant s'adaptait normalement lors d'un test de restriction sodée. Conclusion : Ces données démontrent l'évolution du phénotype avec l'âge avec l'apparition chez l'adulte d'une insuffisance rénale et d'une perte rénale de sodium et de potassium. Le défaut de réabsorption sodée est probablement localisé dans le tubule proximal. Par analogie aux souris déficientes en NHE-3, l'hypothèse pathogénique retenue est qu'avant le développement de l'insuffisance rénale, la perte rénale de NaCl est prévenue par la mise en jeu du rétrocontrôle tubulo-glomérulaire. La réduction néphronique progressive chez les adultes limiterait ce rétrocontrôle et démasquerait la perte rénale de NaCl.PARIS7-Villemin (751102101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Influence de l'insuffisance rénale chronique et de la pollution atmosphérique sur les propriétés mécaniques et fonctionnelles des artères de gros calibre

Les artères de gros calibre, de type élastique subissent des modifications structurales et fonctionnelles en réponse à une modification de leur environnement. L'insuffisance rénale chronique modérée, modèle d'altération hémodynamique et humorale, s'accompagne d'un remodelage artériel spécifique défini par une augmentation du diamètre carotidien sans augmentation de l'épaisseur intima-média résultant en une augmentation de la contrainte circonférentielle et de la rigidité aortique et carotidienne ; ceci en rapport avec des anomalies du métabolisme minéral, d'une surexpression de gènes impliqués dans la migration cellulaire, la prolifération et l'apoptose, et dans la régulation de la matrice extracellulaire. Chez les sujets sains, les polluants atmosphériques sont capables d'altérer la fonction endothéliale. Dans cette thèse, nous avons précisé l'influence des substances humorales et des contraintes hémodynamiques sur le remodelage de la fonction artérielle.Vascular remodeling in large arteries is an active process in response to hemodynamic or humoral changes. Arterial remodeling in chronic renal failure is characterized by carotid enlargement without intima-media thickening determining an increased circumferential wall stress, together with an increased carotid and aortic stiffness. These abnormalities are related with alterations of mineral metabolism, and an overexpression of genes implicated in cell migration, proliferation, apoptosis and in extracellular matrix function. In healthy subjects, air pollutants impaired endothelial function, gaseous pollutants negatively influencing flow mediated dilation of the brachial artery, and particles enhancing reactive hyperemia of small arteries. In this thesis, we precised the influence of hemodynamic and humoral substances on arterial remodeling and function.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Cardiovascular risk assessment through target organ damage: role of carotid to femoral pulse wave velocity

1. Cardiovascular risk prediction relies on classical risk factors such as age, gender, lipids, hypertension, smoking and diabetes. Although the value of such scales of risk is high for populations, its value for individuals is reduced and much influenced by non-modifiable risk factors (age and sex). 2. Biomarkers of risk have been deceiving and the genome-wide scan approach is too recent to have been useful. Target-organ damage may help in selecting patients at high risk and determine the necessity of intervention. 3. Aortic pulse wave velocity, an index of aortic stiffness, has been widely validated as providing additional risk prediction above and beyond classical risk factors and has now entered the 2007 guidelines for hypertension of the European Society of Hypertension. 4. We aim to show that individual prediction of cardiovascular-related death can be improved by taking aortic stiffness into account in a cohort of patients during a longitudinal follow-up. 5. Points to be improved are the homogenization and spreading of the technique of measurement, the establishment of a reference value database and the demonstration of the added value of aortic stiffness screening and stratification in interventional trials

Molybdenum Occupational Study in a French Cohort of Workers

International audienceAbstract Objectives Occupational exposure to molybdenum has been poorly documented to date. Here, we present a retrospective study evaluating urinary molybdenum concentration before and after shift over a period of 2 years in exposed workers. Methods This retrospective study was conducted across eight industrial sites in France and included all workers undergoing medical follow-up for occupational molybdenum exposure. A mean of six sequential samples (before and after shift) was performed for each worker. The urinary molybdenum concentration was determined using a validated method of inductively coupled plasma-mass spectrometry. A mixed linear model was built and linear regression was used to verify the extent to which the urinary molybdenum concentration depends on the age of the workers and the sampling period. Additionally, an analysis based on individual trajectory was also performed. Results Seventy-seven workers were included in the present study. Post-shift urinary molybdenum concentrations were significantly higher than pre-shift values [median (95th percentile) 37.9 (91.1), versus 60.6 (190.0) µg g−1 creatinine, respectively, P &lt; 0.009]. No accumulation of molybdenum over time was observed. The urinary molybdenum concentrations were not influenced by age. Four workers presented high post-shift values as a result of not adhering to protection measures (maxima of 529.8, 359.7, 386.3, and 1459.7 µg g−1 creatinine, respectively). Conclusions To our knowledge, this is the first study of occupational molybdenum exposure in France to include an individual trajectory analysis. No accumulation of molybdenum was seen but high post-shift molybdenum urinary concentrations were observed for some workers. The study emphasizes the importance of molybdenum monitoring in exposed workers

Arterial Remodelling in Chronic Kidney Disease: Impact of Uraemic Toxins and New Pharmacological Approaches

Chronic kidney disease (CKD) is a major public health concern that affects around 10 percent of the world’s population. The severity of CKD is mainly due to the high prevalence of cardiovascular (CV) complications in this population. The aim of this review is to describe the arterial remodelling associated with CKD, to provide a quick overview of the mechanisms involved and to review the recent pharmacological approaches aimed at improving vascular health in CKD. CKD patients are exposed to metabolic and haemodynamic disorders that may affect the CV system. Large artery functional and geometric abnormalities have been well documented in CKD patients and are associated with an increase in arterial stiffness and a maladaptive remodelling. Uraemic toxins, such as indoxyl sulphate, p-cresyl sulphate, protein carbamylation and advanced glycation products, exert various effects on vascular smooth muscle cell functions. The low-grade inflammation associated with CKD may also affect arterial wall composition and remodelling. It is worth noting that the CV risk for CKD patients remains high despite the pharmacological control of traditional CV risk factors, suggesting the need for innovative therapeutic strategies. An interventional study targeting the NLRP3 inflammasome has provided some interesting preliminary results that need to be confirmed, especially in terms of safety

Arterial stiffness and pulse pressure in CKD and ESRD

We recognize that increased systolic pressure is the most challenging form of hypertension today and that pulse pressure as an independent cardiovascular risk factor has focused attention on arterial stiffness and wave reflections as the most important factors determining these pressures. In recent years, many studies emphasized the role of arterial rigidity in the development of cardiovascular diseases, and it was shown that stiffening of arteries is associated with increased cardiovascular mortality and morbidity. Moreover, arterial stiffening is linked to decreased glomerular filtration rate, and is predictive of kidney disease progression and the patient's cardiovascular outcome. Premature vascular aging and arterial stiffening are observed with progression of chronic kidney disease (CKD) and in end-stage renal disease (ESRD). This accelerated aging is associated with outward remodeling of large vessels, characterized by increased arterial radius not totally compensated for by artery wall hypertrophy. Arterial stiffening in CKD and ESRD patients is of multifactorial origin with extensive arterial calcifications representing a major covariate. With aging, the rigidity is more pronounced in the aorta than in peripheral conduit arteries, leading to the disappearance or inversion of the arterial stiffness gradient and less protection of the microcirculation from high-pressure transmission. Various non-pharmacological or pharmacological interventions can modestly slow the progression of arterial stiffness, but arterial stiffness is, in part, pressure dependent and treatments able to stop the process mainly include antihypertensive drugs