Cardiovascular calcification is a growing burden and a leading contributor to acute cardiovascular events, but no therapeutics are currently available. Recently, Choi et al. [(1)][1] put forward dipeptidyl peptidase (DPP)-4 as a new pharmacological target to prevent aortic valve calcification. DPP-

Despite the availability of new oral anticoagulants, vitamin K antagonists (VKA, such as fluindione, acenocoumarol or warfarin) remain currently the goal standard medicines for oral prevention or treatment of thromboembolic disorders. They inhibit the cycle of the vitamin K and its participation in the enzymatic gamma-carboxylation of many proteins. The VKA prevent the activation of the vitamin K-dependent blood clotting factors limiting thus the initiation of the coagulation cascade. But other proteins are vitamin K-dependent and also remain inactive in the presence of VKA. This is the case of matrix Gla-protein (MGP), a protein that plays a major inhibitory role in the development of vascular calcifications. Several experimental and epidemiological results suggest that the use of the VKA could promote the development of vascular calcifications increasing thus the cardiovascular risk. This risk seems to be higher in patients with chronic kidney disease or mellitus diabetes who are more likely to develop vascular calcifications, and may be due to a decrease of the MGP activity. This review aims at summarizing the data currently available making vascular calcifications the probably underestimated side effects of VKA. (C) 2016 Societe francaise de pharmacologie et de therapeutique. Published by Elsevier Masson SAS. All rights reserved.

Despite the availability of new oral anticoagulants, vitamin K antagonists (VKA, such as fluindione, acenocoumarol or warfarin) remain currently the goal standard medicines for oral prevention or treatment of thromboembolic disorders. They inhibit the cycle of the vitamin K and its participation in the enzymatic gamma-carboxylation of many proteins. The VKA prevent the activation of the vitamin K-dependent blood clotting factors limiting thus the initiation of the coagulation cascade. But other proteins are vitamin K-dependent and also remain inactive in the presence of VKA. This is the case of matrix Gla-protein (MGP), a protein that plays a major inhibitory role in the development of vascular calcifications. Several experimental and epidemiological results suggest that the use of the VKA could promote the development of vascular calcifications increasing thus the cardiovascular risk. This risk seems to be higher in patients with chronic kidney disease or mellitus diabetes who are more likely to develop vascular calcifications, and may be due to a decrease of the MGP activity. This review aims at summarizing the data currently available making vascular calcifications the probably underestimated side effects of VKA.

La colchicine est un alcaloïde utilisé pour ses propriétés anti-inflammatoires en prophylaxie ou dans le traitement de la crise aiguë de goutte et dans d’autres maladies à composante inflammatoire telles que la fièvre méditerranéenne familiale ou la maladie de Behçet. Sa toxicité limite cependant son utilisation. Les intoxications à la colchicine sont rares mais potentiellement graves et très souvent mortelles à ce jour. Elles sont responsables d’une atteinte multi-viscérale allant jusqu’au décès dans les cas les plus graves, le plus souvent par défaillance cardiaque et/ou respiratoire. Elles peuvent être observées suite à un défaut d’élimination, à une interaction médicamenteuse ou à une ingestion massive de colchicine. Nous rapportons ici 3 cas d’intoxications aiguës survenues secondairement à une prise massive de colchicine dans un contexte suicidaire. Dans les 3 cas, une mesure des concentrations plasmatiques de colchicine par chromatographie liquide couplée à une détection par spectrométrie de masse en tandem a permis de confirmer l’intoxication. Dans le cas le plus sévère, une mesure régulière des concentrations de colchicine a permis de suivre l’évolution de l’intoxication.

Objective: The relationship between blood pressure (BP) and cardiovascular disease (CVD) has been extensively documented. However the benefit of anti-hypertensive drugs is less pronounced for coronary prevention than for stroke prevention. Because coronary and cerebral circulation obey different regulatory mechanisms we questioned the role of BP level per se (estimated by mean BP (MBP)) and aortic stiffness (estimated by aortic atherosclerosis and pulse pressre (PP)) on 2 different outcomes: acute myocardial infarction (MI) and acute stroke. The analysis was also repeated for 2 more liberal outcomes: coronary heart disease and cerebrovascular disease. Design and method: 1031 subjects referred in the seventies for hypertension work-up were included and outcomes assessed 30 years later. A 3-grade aortic atherosclerotic score was built on the aortography, initially performed to seek for renal artery stenosis. Results: At baseline, mean age was 44 years with two third of men; MBP and PP were 136 ± 22 and 77 ± 23 mmHg, respectively. MBP, PP, and aortic atherosclerotic score were all significantly associated with MI and stroke in univariate analysis (p < 0.001 for all). In multivariate analysis taking into account the major risk factors (see Table on the following page), PP and atherosclerotic score, but MBP appeared as significant predictors of MI. On the contrary, only MBP appeared as a significant predictor of stroke. Similar results were obtained for coronary heart disease and cerebrovascular disease.Conclusions: These results highlight that MI is primitively a vascular problem tightly related to aortic stiffness; this may explain why strategy only aimed at lowering BP do not confer a complete reversion of the risk (i.e. a residual risk remains despite treatment). Some new strategy aimed at aortic destiffnening could be more efficient on this outcome. On the contrary, stroke is a “pure BP disease”. No destiffening is needed provided that BP is lowered.

L'obésité, facteur de risque cardio-vasculaire est associée à des concentrations circulantes augmentées de marqueurs de l'inflammation, le tissu adipeux (TA) est une source de ces facteurs pro-inflammatoires. Au niveau de l'aorte, le tissu adipeux péri-artériel (TAPA) peut avoir des effets importants et directs sur la paroi artérielle et donc qu'un état inflammatoire élevé et un profil d'expression génique et de sécrétion de molécules défavorable peuvent favoriser directement le développement de l'athérome. Pour tester ces hypothèses nous avons mesuré l'expression de gènes de l'inflammation dans du tissu adipeux péri-artériel et sous-cutané humain et dans du tissu adipeux épididymaire (TAE) et péri-aortique de rats Zucker obèses. Du tissu adipeux péricarotidien humain au voisinage immédiat de la plaque (TAPAp) et à distance de la plaque (TAPAs) et du tissu adipeux sous cutané du cou (TAssC) ont été recueillis chez huit sujets diabétiques et hypertendus opérés pour athérome carotidien. Parallèlement nous avons prélevé du tissu adipeux épididymaire (TAE) et du TAPA de rats Zuckers obèses, modèle d'insulinorésistance, et de leurs contrôles (étudiés à l'âge de 7, 14 et 21 semaines). Les ARNm (IL-6, TNFα, MCP-1) ont été mesurés par PCR quantitative. Les comparaisons ont été faites par analyse de variance (appariée). Les concentrations d'ARNm de l'IL-6 sont plus élevées dans le tissu adipeux au voisinage de la plaque (TAPAp) que dans celui situé à distance de la plaque (TAPAs) (p < 0,01) et que dans le TAssC (p < 0,05). Il en est de même pour MCP-1 (p < 0,05 vs TAPAs et TAssC). Il n'y a par contre pas de différence pour TNFá. Les ARNm de TNFα ont augmenté à 14 semaines (p < 0,01) dans le TAPA des rats Zucker obèses comparativement aux contrôles. Alors qu'au niveau du TAE aucune différence significative de l'expression de ce gène n'a été enregistrée. L'expression de MCP-1 est également plus élevée dans le TAPA des rats Zucker obèses à 14 et à 21 semaines. Les concentrations d'ARNm de MCP-1 sont similaires dans le TAE des rats obèses et contrôles. Ces résultats préliminaires montrent que le TAPA au voisinage de la plaque d'athérome ainsi que celui provenant des rats Zucker obèses est inflammatoire mais ne permettent pas de conclure sur un rôle éventuel de cette inflammation dans l'évolution de l'athérome. Les auteurs déclarent ne pas avoir d'intérêt direct ou indirect (financier ou en nature) avec un organisme privé, industriel ou commercial en relation avec le sujet présenté.

Datura belongs to the family of Solanaceae. It is long known for its hallucinogenic properties. All parts of the plant are toxic and contain alkaloids such as hyoscyamine, atropine and scopolamine. They produce a parasympatholytic syndrome related to the antagonism of central and peripheral muscarinic receptors. We report here the case of a 27-year-old-man admitted to an intensive care unit for a coma after voluntary datura consumption. Research and quantification of alkaloids by liquid chromatography coupled with tandem mass spectrometry have confirmed acute datura poisoning. Blood concentrations of scopolamine measured on samples taken 9 and 18 hours after datura intake were respectively of 1.2 ng/mL and 0.6 ng/mL. At the same time, urinary concentrations of scopolamine were measured at 132 ng/mL and 71 ng/mL. Atropine was not found in any samples. The consumption of datura for recreational purposes is common. The research of hallucinogenic effects often leads to an acute intoxication with a favourable issue. The low plasma concentrations and short elimination half-life of alkaloids can delay diagnosis if their research and quantification by a sufficiently sensitive method was not prescribed. In this case, only hair analysis is possible to identify datura consumption. (C) 2015 Societe Francaise de Toxicologie Analytique. Published by Elsevier Masson SAS. All rights reserved.

Objective: The relationship between blood pressure (BP) and cardiovascular disease (CVD) has been extensively documented. However the benefit of anti-hypertensive drugs is less pronounced for coronary prevention than for stroke prevention. Because coronary and cerebral circulation obey different regulatory mechanisms we questioned the role of BP level per se (estimated by mean BP (MBP)) and aortic stiffness (estimated by aortic atherosclerosis and pulse pressre (PP)) on 2 different outcomes: acute myocardial infarction (MI) and acute stroke. The analysis was also repeated for 2 more liberal outcomes: coronary heart disease and cerebrovascular disease. Design and method: 1031 subjects referred in the seventies for hypertension work-up were included and outcomes assessed 30 years later. A 3-grade aortic atherosclerotic score was built on the aortography, initially performed to seek for renal artery stenosis. Results: At baseline, mean age was 44 years with two third of men; MBP and PP were 136 ± 22 and 77 ± 23 mmHg, respectively. MBP, PP, and aortic atherosclerotic score were all significantly associated with MI and stroke in univariate analysis (p < 0.001 for all). In multivariate analysis taking into account the major risk factors (see Table on the following page), PP and atherosclerotic score, but MBP appeared as significant predictors of MI. On the contrary, only MBP appeared as a significant predictor of stroke. Similar results were obtained for coronary heart disease and cerebrovascular disease.Conclusions: These results highlight that MI is primitively a vascular problem tightly related to aortic stiffness; this may explain why strategy only aimed at lowering BP do not confer a complete reversion of the risk (i.e. a residual risk remains despite treatment). Some new strategy aimed at aortic destiffnening could be more efficient on this outcome. On the contrary, stroke is a “pure BP disease”. No destiffening is needed provided that BP is lowered.

Objective: The implication of the renin-angiotensin-aldosterone system (RAAS) in atheroma development is well described. However, a complete view of the local RAAS in atheroma is still missing. In this study we aimed to reveal the organization of RAAS in atheroma at the transcriptomic level and identify the transcriptional regulators behind it. Design and method: Extended RAAS (extRAAS) was defined as the set of 37 genes coding for classical and novel RAAS participants (Figure 1). Five microarray datasets containing overall 590 samples representing carotid and peripheral atheroma were downloaded from the GEO database. Correlation-based hierarchical clustering (R software) of extRAAS genes within each dataset allowed the identification of modules of co-expressed genes. Reproducible co-expression modules across datasets were then extracted. Transcription factors (TFs) having common binding sites (TFBSs) in the promoters of coordinated genes were identified using the Genomatix database tools and analyzed for their correlation with extRAAS genes in the microarray datasets. Results: Expression data revealed the expressed extRAAS components and their relative abundance displaying the favored pathways in atheroma. Three co-expression modules with more than 80% reproducibility across datasets were extracted. Two of them (M1 and M2) contained genes coding for angiotensin metabolizing enzymes involved in different pathways: M1 included ACE, MME, RNPEP, and DPP3, in addition to 7 other genes; and M2 included CMA1, CTSG, and CPA3. The third module (M3) contained genes coding for receptors known to be implicated in atheroma (AGTR1, MR, GR, LNPEP, EGFR and GPER). M1 and M3 were negatively correlated in 3 of 5 datasets. We identified 19 TFs that have enriched TFBSs in the promoters of genes of M1, and two for M3, but none was found for M2. Among the extracted TFs, ELF1, MAX, and IRF5 showed significant positive correlations with peptidase-coding genes from M1 and negative correlations with receptors-coding genes from M3 (p < 0.05). Conclusions: The identified co-expression modules display the transcriptional organization of local extRAAS in human carotid atheroma. The identification of several TFs potentially associated to extRAAS genes may provide a frame for the discovery of atheroma-specific modulators of extRAAS activity. Figure. No caption available.

Nous rapportons l’expérience du centre hospitalo-universitaire de Lyon concernant la dénervation rénale pour le traitement de l’hypertension artérielle résistante. Sur une période d’un an, 17 patients (12 hommes/5 femmes) ont été traités par une procédure de dénervation rénale. L’âge moyen était de 56,5 ± 11,5 ans, l’indice de masse corporelle (IMC) de 33 ± 5 kg/m2 et la mesure ambulatoire de la pression artérielle (MAPA) des 24 heures de 157 ± 16/87 ± 13 mmHg avec en moyenne 4,2 ± 1,5 traitements anti-hypertenseurs. Nous n’avons pas observé de complications péri- ou postopératoires dans notre cohorte. Après un suivi médian de 3 mois et un nombre de traitements anti-hypertenseurs stable (n = 4,2 ± 1,2), la baisse de pression artérielle obtenue en consultation est en moyenne de 20 ± 15 mmHg (p < 0,001) pour la pression artérielle systolique et de 10 ± 13 mmHg (p = 0,014) pour la pression artérielle diastolique à 1 mois (n = 17). Pour les 6 patients dont le suivi est supérieur à 3 mois, la baisse de pression artérielle obtenue sur la MAPA des 24 heures est 17,5 ± 14,9 (p = 0,027) pour la systolique et 10,5 ± 9,6 (p = 0,029) pour la diastolique. Cinq des 6 patients ont une MAPA des 24 heures contrôlée <130/80 mmHg et nous observons une diminution des signes d’hypertrophie ventriculaire gauche électriques : diminution de l’onde R en aVL de 4 ± 3 mm (p = 0,031), de l’index de Sokolow de 3 ± 3 mm (p = 0,205), de l’index de Cornell de 9 ± 7 mm (p = 0,027) et du produit du Cornell de 1310 ± 1104 (p = 0,027). Nos résultats sont en accord avec les données observées dans les autres centres. La réponse manométrique est significative, mais la variation interindividuelle est importante. La sécurité de la technique est acceptable. We report the first experience of Lyon's university hospital regarding renal denervation to treat patients with resistant essential hypertension. Over a one-year period, 17 patients were treated (12 men, 5 women) with renal denervation. Baseline characteristics were as follows: age 56.5 ± 11.5 years, BMI 33 ± 5 kg/m2 and ambulatory blood pressure 157 ± 16/87 ± 13 mmHg with 4.2 ± 1.5 anti-hypertensive treatment. We did not observe per procedural and early complications. After a median follow-up of 3 months and with the same anti-hypertensive treatment, office systolic blood pressure (SBP) and diastolic blood pressure (DBP) decrease respectively of 20 ± 15 (P < 0.001) and 10 ± 13 mmHg (P = 0.014) (n = 17). After six months of follow-up, ambulatory blood pressure (ABPM) decrease of 17.5 ± 14.9 mmHg (P = 0.027) for SBP and of 10.5 ± 9.6 mmHg (P = 0.029) for DBP (n = 6). Among these patients, five of them were controlled (ABPM inferior to 130/80 mmHg) and electrical left ventricular hypertrophy indexes decreased: R wave in aVL lead of 4 ± 3 mm (P = 0.031), Sokolow index of 3 ± 3 mm (P = 0.205), Cornell voltage criterion of 9 ± 7 mm (P = 0.027) and Cornell product of 1310 ± 1104 (P = 0.027). Our results are in accordance with data from other centers. On average blood pressure decreases significantly but important inter individual variations are observed. The procedure seems safe.

Current antihypertensive strategies do not take into account that individual characteristics may influence the magnitude of blood pressure (BP) reduction. Guidelines promote trial-and-error approaches with many different drugs. We conducted the Identification of the Determinants of the Efficacy of Arterial blood pressure Lowering drugs (IDEAL) Trial to identify factors associated with BP responses to perindopril and indapamide. IDEAL was a cross-over, double-blind, placebo-controlled trial, involving four 4-week periods: indapamide, perindopril and two placebo. Eligible patients were untreated, hypertensive and aged 25–70 years. The main outcome was systolic BP (SBP) response to drugs. The 112 participants with good compliance had a mean age of 52. One in every three participants was a woman. In middle-aged women, the SBP reduction from drugs was −11.5 mm Hg (indapamide) and −8.3 mm Hg (perindopril). In men, the response was significantly smaller: −4.8 mm Hg (indapamide) and −4.3 (perindopril) (P for sex differences 0.001 and 0.015, respectively). SBP response to perindopril decreased by 2 mm Hg every 10 years of age in both sexes (P=0.01). The response to indapamide increased by 3 mm Hg every 10 years of age gradient in women (P=0.02). Age and sex were important determinants of BP response for antihypertensive drugs in the IDEAL population. This should be taken into account when choosing drugs a priori.

AIM:We report the first experience of Lyon's university hospital regarding renal denervation to treat patients with resistant essential hypertension. PATIENTS AND METHODS:Over a one-year period, 17 patients were treated (12 men, 5 women) with renal denervation. Baseline characteristics were as follows: age 56.5±11.5 years, BMI 33±5kg/m(2) and ambulatory blood pressure 157±16/87±13mmHg with 4.2±1.5 anti-hypertensive treatment. RESULTS:We did not observe intra-operative or early complications. After a median follow-up of 3 months and with the same anti-hypertensive treatment, office systolic blood pressure (SBP) and diastolic blood pressure (DBP) decrease respectively of 20±15 (P<0.001) and 10±13mmHg (P=0.014) (n=17). After six months of follow-up, ambulatory blood pressure (ABPM) decrease of 17.5±14.9mmHg (P=0.027) for SBP and of 10.5±9.6mmHg (P=0.029) for DBP (n=6). Among these patients, five of them were controlled (ABPM inferior to 130/80mmHg) and electrical left ventricular hypertrophy indexes decreased: R wave in aVL lead of 4±3mm (P=0.031), Sokolow index of 3±3mm (P=0.205), Cornell voltage criterion of 9±7mm (P=0.027) and Cornell product of 1310±1104 (P=0.027). CONCLUSION:Our results are in accordance with data from other centers. On average blood pressure decreases significantly but important inter individual variations are observed. The procedure seems safe.

<正>该研究收集高血压患者426例,年龄(51.2±13.8)岁,收缩压(155.6±21.1)mmHg(1mmHg=0.133kPa)。根据4种不同路径评估法(直接、实时、减去、估计),分别计算4次颈股动脉脉搏波传导速度(pulse wave velocity,PWV)。观测全因死亡和主要心血管事件发病率。采用C指数分析PWV预测的准

PURPOSE:Vascular calcification was considered to be a passive, degenerative, and end-stage process of vascular disease. However, bone associated proteins such as bone morphogenetic proteins, osteopontin, osteonectin, osteocalcin, and matrix Gla protein (MGP) have been found in the calcified atherosclerotic lesions. We studied by microarray analysis whether intact tissue and carotid plaque from the same patient differ in transcriptional profiling in response to arterial calcification.MATERIAL AND METHODS:mRNA gene expression was measured by an Affymetrix GeneChip Human Gene 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 68 specimens of endarterectomy from 34 patients.RESULTS:Integrin-binding sialoprotein (IBSP) was found to be differentially expressed. IBSP mRNA is over expressed in atheroma plaque (3.74 fold, p = 1.41E-09) in an intraindividual comparison. Besides, Carbonic anhydrase II (CA2) which known to be a putative calcification inhibitory molecule is over expressed more than 1.7 fold in carotid plaque (p = 1.26E-06).CONCLUSION:Although further evidence is needed, our results support previously available data. To our knowledge, this is the first report comparing gene expression between intact arterial tissue and carotid plaque using microarray analysis in order to identify calcification related genes. We suggest that plaques show a more pronounced induction of IBSP that may cause arterial calcification.

Aim. - Lipogenesis is expressed in vascular smooth muscle cells (VSMCs), and such in situ lipogenesis could be providing the fatty acids for triglyceride synthesis and cholesterol esterification, and contributing to lipid accumulation in the arterial wall. This study investigated both the expression and regulation of lipogenesis in VSMCs to determine if they are modified in Psammomys obesus gerbils fed a high-fat diet as a model of insulin resistance and diabetes.Methods. - Aortas were collected from diabetic and non-diabetic P. obesus for histological examination, measurement of lipogenic gene expression and VSMC culture.Results. - The aortas of diabetic animals exhibited lipid deposits and foam cells as well as disorganization of elastic fibres. However, lipogenic gene expression was not modified. VSMCs in vitro from the aortas of diabetic animals had, compared with cells from non-diabetic animals, lower mRNA levels of SREBP-1c and ChREBP. An adipogenic medium stimulated moderate FAS and ACC1 expression in cells from both diabetic and non-diabetic animals, but glucose and insulin on their own had no such stimulatory action. Also, triiodothyronine (T3) had a clear stimulatory action, while angiotensin It had a moderate effect, in cells from non-diabetic P. obesus, but not from diabetic animals, whereas LXR agonists stimulated lipogenesis in cells from both animal groups.Conclusion. - Lipogenesis is expressed in the arterial walls and VSMCs of P. obesus. However, its expression was not increased in diabetes, and did not respond to either T3 or angiotensin II. Therefore, lipogenesis in situ is unlikely to contribute to the accumulation of lipids in the arterial walls of diabetic P. obesus gerbils. (C) 2010 Elsevier Masson SAS. All rights reserved.