La génétique de l'hypertension: rôle des gènes CYP3A5 et ABCB1 dans le contrôle de la tension artérielle

Des données récentes suggèrent que les gènes ABCB1 et CYP3A5 sont impliqués dans le contrôle de la tension artérielle chez l'homme. Les gènes ABCB1 et CYP3A5 sont bien connus pour interagir l'un avec l'autre dans le métabolisme et le transport de nombreux médicaments, mais on sait peu de choses sur leurs rôles dans les processus physiologiques endogènes chez l'homme. Si les gènes ABCB1 et CYP3A5 influencent la tension artérielle par leur action sur des substrats endogènes, comme l'aldostérone, cela pourrait avoir des conséquences importantes pour le traitement des sujets hypertendus ainsi que dans le domaine de la pharmacogénétique. Ces gènes semblent influencer la tension artérielle par l'intermédiaire du système rénine-angiotensin- aldostérone via la réabsorption tubulaire rénale de sodium. Ces résultats soulignent l'importance de tenir compte des interactions gène-gène et le rôle clé de la consommation en sel comme modificateur d'effet en génétique de l'hypertension. Si ces résultats sont confirmés dans plusieurs études indépendantes, cela ouvre la voie vers un nouveau mécanisme de contrôle de la tension artérielle chez l'homme.

Etiology of ethnic differences in childhood spirometry.

OBJECTIVES: Age- and height-adjusted spirometric lung function of South Asian children is lower than those of white children. It is unclear whether this is purely genetic, or partly explained by the environment. In this study, we assessed whether cultural factors, socioeconomic status, intrauterine growth, environmental exposures, or a family and personal history of wheeze contribute to explaining the ethnic differences in spirometric lung function. METHODS: We studied children aged 9 to 14 years from a population-based cohort, including 1088 white children and 275 UK-born South Asians. Log-transformed spirometric data were analyzed using multiple linear regressions, adjusting for anthropometric factors. Five different additional models adjusted for (1) cultural factors, (2) indicators of socioeconomic status, (3) perinatal data reflecting intrauterine growth, (4) environmental exposures, and (5) personal and family history of wheeze. RESULTS: Height- and gender-adjusted forced vital capacity (FVC) and forced expired volume in 1 second (FEV1) were lower in South Asian than white children (relative difference -11% and -9% respectively, P < .001), but PEF and FEF50 were similar (P ≥ .5). FEV1/FVC was higher in South Asians (1.8%, P < .001). These differences remained largely unchanged in all 5 alternative models. CONCLUSIONS: Our study confirmed important differences in lung volumes between South Asian and white children. These were not attenuated after adjustment for cultural and socioeconomic factors and intrauterine growth, neither were they explained by differences in environmental exposures nor a personal or family history of wheeze. This suggests that differences in lung function may be mainly genetic in origin. The implication is that ethnicity-specific predicted values remain important specifically for South Asian children.

Le traitement pharmacologique de l'hypertension artérielle est-il bénéfique chez les personnes âgées? : revue Cochrane pour le praticien

Cet article présente les résultats de la revue systématique: Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD000028. PMID: 19821263

Growing up with bilateral hippocampal atrophy: from childhood to teenage.

The respective roles of the medial temporal lobe (MTL) structures in memory are controversial. Some authors put forward a modular account according to which episodic memory and recollection-based processes are crucially dependent on the hippocampal formation whereas semantic acquisition and familiarity-based processes rely on the adjacent parahippocampal gyri. Others defend a unitary view. We report the case of VJ, a boy with developmental amnesia of most likely perinatal onset diagnosed at the age of 8. Magnetic resonance imaging (MRI), including quantitative volumetric measurements of the hippocampal formation and of the entorhinal, perirhinal, and temporopolar cortices, showed severe, bilateral atrophy of the hippocampal formation, fornix and mammillary bodies; by contrast, the perirhinal cortex was within normal range and the entorhinal and temporopolar cortex remained within two standard deviations (SDs) from controls' mean. We examined the development of his semantic knowledge from childhood to teenage as well as his recognition and cued recall memory abilities. On tasks tapping semantic memory, VJ increased his raw scores across years at the same rate as children from large standardisation samples, except for one task; he achieved average performance, consistent with his socio-educational background. He performed within normal range on 74% of recognition tests and achieved average to above average scores on 42% of them despite very severe impairment on 82% of episodic recall tasks. Both faces and landscapes-scenes gave rise to above average scores when tested with coloured stimuli. Cued recall, although impaired, was largely superior to free recall. This case supports a modular account of the MTL with episodic, but not semantic memory depending on the hippocampal formation. Furthermore, the overall pattern of findings is consistent with evidence from both brain-damaged and neuroimaging studies indicating that recollection requires intact hippocampal formation and familiarity relies, at least partly, on the adjacent temporal lobe cortex.

Screening for elevated blood pressure in children and adolescents: a critical appraisal.

Although screening for elevated blood pressure (BP) in adults is beneficial, evidence of its beneficial effects in children is not clear. Elevated BP in children is associated with atherosclerosis early in life and tracks across the life course. However, because of the high variability in BP, tracking is weak, and having an elevated BP in childhood has a low predictive value for having elevated BP later in life. The absolute risk of cardiovascular diseases associated with a given level of BP in childhood and the long-term effect of treatment beginning in childhood are not known. No study has experimentally evaluated the benefits and harm of BP screening in children. One modeling study indicates that BP screen-and-treat strategies in adolescents are moderately cost-effective but less cost-effective than population-wide interventions to decrease BP for the reduction of coronary heart diseases. The US National Heart, Lung, and Blood Institute and the European Society of Hypertension recommend that children 3 years of age and older have their BP measured during every health care visit. According to the US Preventive Services Task Force, there is no sufficient evidence to recommend for or against screening, but their recommendations have to be updated. Whether the benefits of universal BP screening in children outweigh the harm has to be determined. Studies are needed to assess the absolute risk of cardiovascular diseases associated with elevated BP in childhood, to evaluate how to simplify the identification of elevated BP, to evaluate the long-term benefits and harm of treatment beginning in childhood, and to compare universal and targeted screening strategies.

Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study.

Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G is associated with respiratory chain complex I deficiency and has been described as a rare cause of mostly adult-onset slowly progressive myopathy. Five families with 11 patients have been described so far; 5 of them died young due to cardiorespiratory failure. Here, we report on a segregation study in a family with an index patient who already presented at the age of 18 months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8 years, the patient is wheel-chair bound, requires nocturnal assisted ventilation, and suffers from recurrent respiratory infections. Severe complex I deficiency and nearly homoplasmy for m.3302A > G were found in muscle. We collected blood, hair, buccal swabs and muscle biopsies from asymptomatic adults in this pedigree and determined heteroplasmy levels in these tissues as well as OXPHOS activities in muscle. All participating asymptomatic adults had normal OXPHOS activities. In contrast to earlier reports, we found surprisingly little variation of heteroplasmy levels in different tissues of the same individual. Up to 45% mutation load in muscle and up to 38% mutation load in other tissues were found in non-affected adults. The phenotypic spectrum of tRNA(Leu(UUR)) m.3302A > G mutation seems to be wider than previously described. A threshold of more than 45% heteroplasmy in muscle seems to be necessary to alter complex I activity leading to clinical manifestation. The presented data may be helpful for prognostic considerations and counseling in affected families.

Parent-child agreement and prevalence estimates of diagnoses in childhood: direct interview versus family history method.

Diagnostic information on children is typically elicited from both children and their parents. The aims of the present paper were to: (1) compare prevalence estimates according to maternal reports, paternal reports and direct interviews of children [major depressive disorder (MDD), anxiety and attention-deficit and disruptive behavioural disorders]; (2) assess mother-child, father-child and inter-parental agreement for these disorders; (3) determine the association between several child, parent and familial characteristics and the degree of diagnostic agreement or the likelihood of parental reporting; (4) determine the predictive validity of diagnostic information provided by parents and children. Analyses were based on 235 mother-offspring, 189 father-offspring and 128 mother-father pairs. Diagnostic assessment included the Kiddie-schedule for Affective Disorders and Schizophrenia (K-SADS) (offspring) and the Diagnostic Interview for Genetic Studies (DIGS) (parents and offspring at follow-up) interviews. Parental reports were collected using the Family History - Research Diagnostic Criteria (FH-RDC). Analyses revealed: (1) prevalence estimates for internalizing disorders were generally lower according to parental information than according to the K-SADS; (2) mother-child and father-child agreement was poor and within similar ranges; (3) parents with a history of MDD or attention deficit hyperactivity disorder (ADHD) reported these disorders in their children more frequently; (4) in a sub-sample followed-up into adulthood, diagnoses of MDD, separation anxiety and conduct disorder at baseline concurred with the corresponding lifetime diagnosis at age 19 according to the child rather than according to the parents. In conclusion, our findings support large discrepancies of diagnostic information provided by parents and children with generally lower reporting of internalizing disorders by parents, and differential reporting of depression and ADHD by parental disease status. Follow-up data also supports the validity of information provided by adolescent offspring.

European Society of Hypertension practice guidelines for ambulatory blood pressure monitoring.

Given the increasing use of ambulatory blood pressure monitoring (ABPM) in both clinical practice and hypertension research, a group of scientists, participating in the European Society of Hypertension Working Group on blood pressure monitoring and cardiovascular variability, in year 2013 published a comprehensive position paper dealing with all aspects of the technique, based on the available scientific evidence for ABPM. The present work represents an updated schematic summary of the most important aspects related to the use of ABPM in daily practice, and is aimed at providing recommendations for proper use of this technique in a clinical setting by both specialists and practicing physicians. The present article details the requirements and the methodological issues to be addressed for using ABPM in clinical practice, The clinical indications for ABPM suggested by the available studies, among which white-coat phenomena, masked hypertension, and nocturnal hypertension, are outlined in detail, and the place of home measurement of blood pressure in relation to ABPM is discussed. The role of ABPM in pharmacological, epidemiological, and clinical research is also briefly mentioned. Finally, the implementation of ABPM in practice is considered in relation to the situation of different countries with regard to the reimbursement and the availability of ABPM in primary care practices, hospital clinics, and pharmacies.

Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension.

The 15q24.1 locus, including CYP1A2, is associated with blood pressure (BP). The CYP1A2 rs762551 C allele is associated with lower CYP1A2 enzyme activity. CYP1A2 metabolizes caffeine and is induced by smoking. The association of caffeine consumption with hypertension remains controversial. We explored the effects of CYP1A2 variants and CYP1A2 enzyme activity on BP, focusing on caffeine as the potential mediator of CYP1A2 effects. Four observational (n = 16 719) and one quasi-experimental studies (n = 106) including European adults were conducted. Outcome measures were BP, caffeine intake, CYP1A2 activity and polymorphisms rs762551, rs1133323 and rs1378942. CYP1A2 variants were associated with hypertension in non-smokers, but not in smokers (CYP1A2-smoking interaction P = 0.01). Odds ratios (95% CIs) for hypertension for rs762551 CC, CA and AA genotypes were 1 (reference), 0.78 (0.59-1.02) and 0.66 (0.50-0.86), respectively, P = 0.004. Results were similar for the other variants. Higher CYP1A2 activity was linearly associated with lower BP after quitting smoking (P = 0.049 and P = 0.02 for systolic and diastolic BP, respectively), but not while smoking. In non-smokers, the CYP1A2 variants were associated with higher reported caffeine intake, which in turn was associated with lower odds of hypertension and lower BP (P = 0.01). In Mendelian randomization analyses using rs1133323 as instrument, each cup of caffeinated beverage was negatively associated with systolic BP [-9.57 (-16.22, -2.91) mmHg]. The associations of CYP1A2 variants with BP were modified by reported caffeine intake. These observational and quasi-experimental results strongly support a causal role of CYP1A2 in BP control via caffeine intake.

Ambulatory Blood Pressure and Adherence Monitoring: Diagnosing Pseudoresistant Hypertension.

A small proportion of the treated hypertensive population consistently has a blood pressure greater than 140/90 mm Hg despite a triple therapy including a diuretic, a calcium channel blocker, and a blocker of the renin-angiotensin system. According to guidelines, these patients have so-called resistant hypertension. The prevalence of this clinical condition is higher in tertiary than primary care centers and often is associated with chronic kidney disease, diabetes, obesity, and sleep apnea syndrome. Exclusion of pseudoresistant hypertension using ambulatory or home blood pressure monitoring is a crucial step in the investigation of patients with resistant hypertension. Thus, among the multiple factors to consider when investigating patients with resistant hypertension, ambulatory blood pressure monitoring should be performed very early. Among other factors to consider, physicians should investigate patient adherence to therapy, assess the adequacy of treatment, exclude interfering factors, and, finally, look for secondary forms of hypertension. Poor adherence to therapy accounts for 30% to 50% of cases of resistance to therapy depending on the methodology used to diagnose adherence problems. This review discusses the clinical factors implicated in the pathogenesis of resistant hypertension with a particular emphasis on pseudoresistance, drug adherence, and the use of ambulatory blood pressure monitoring for the diagnosis and management of resistant hypertension.

Hypertension. L'etude ACCOMPLISH: des résultats vraiment inattendus [The ACCOMPLISH trial: are results really unexpected?]

The ACCOMPLISH trial consists of a randomized morbidity-mortality study involving 11506 hypertensive patients at high cardiovascular risk, randomly allocated to a fixed dose combination containing an angiotensin converting enzyme inhibitor (B, benazepril) and either a calcium antagonist (A, amlodipine) or a diuretic (HCTZ, hydrochlorothiazide). The target blood pressure (< 140/90 mmHg) was achieved after a 6 month titration period in 75.4% of patients receiving B+A, versus 72.4% in those on B + HCTZ. Over a mean follow-up of 3 years, the B + A drug regimen was found to reduce significantly more effectively the relative risk cardiovascular mortality (-20%), fatal and non fatal myocardial infarction (-22%) and coronary revascularization (-14%), appearing therefore particularly effective to prevent complications due to myocardial ischemia.

Neuro-developmental follow-up of neonates treated with magnesium sulfate for persistent pulmonary hypertension

Rapport de synthèse : DEVENIR NEURO-DEVELOPPEMENTAL DE NOUVEAU-NES TRAITES PAR DU SULFATE DE MAGNESIUM POUR UNE HYPERTENSION PULMONAIRE PERSISTANTE L'hypertension pulmonaire persistante du nouveau-né (HTPP) est un trouble de l'adaptation post-natale de la circulation pulmonaire caractérisé par une défaillance de la diminution normale des résistances vasculaires pulmonaires, accompagné d'un shunt droite-gauche, résultant en une hypoxémie profonde. C'est une pathologie sévère nécessitant des soins intensifs avec un risque augmenté de handicaps neurologiques chez les survivants. Le traitement de l'HTPP du nouveau-né inclut une ventilation mécanique ainsi que différents agents pharmacologiques pour dilater les vaisseaux pulmonaires, dont le sulfate de magnésium (MgSO4) à hautes doses par voie intraveineuse et le monoxyde d'azote par voie inhalée (iN0). Le MgSO4 est une alternative thérapeutique de l'HTPP du nouveau-né avec peu d'effets secondaires et une mortalité basse. Il a aussi été démontré que le MgSO4 est un traitement de l'HTPP du nouveau-né autant efficace que le iN0 et moins coüteux. Des études sur le suivi neuro-développemental de nouveau-nés avec HTPP traités selon différentes méthodes ont été publiées reportant des taux élevés de handicaps majeurs et mineurs. Plus récemment, des études de suivi après traitement par iN0 ont montré des taux plus bas qu'avec des traitements antérieurs. Le devenir neuro-développemental àlong terme d'enfants traités avec du MgSO4 n'a pas été documenté. Le but de cette étude est de décrire le développement des enfants qui ont présenté une HTPP traitée seulement avec du MgS04, de reporter l'incidence de handicaps majeurs et mineurs, et de les comparer à un groupe contrôle d'enfants sains du même âge ainsi qu'aux données de la littérature. La population consiste en 33 nouveau-nés traités pour une HTPP avec seulement du MgSO4 (groupe étude) et 32 nouveau-nés à terme sains (groupe contrôle). Un suivi neurodéveloppemental standardisé et approfondi a été effectué aux âges clés de 18 mois et 5 ans. Les taux de handicaps majeurs à 18 mois et 5 ans dans le groupe étude étaient de 6% et 11,4% respectivement, et de 0% aux deux âges dans le groupe contrôle. Les taux de handicaps mineurs aux mêmes âges étaient de 3% et 26,9% pour le groupe étude, et de 0% et 26,1% pour le groupe contrôle. Les quotients développementaux moyens à 18 mois étaient de 106,6 (DS 1,6) dans le groupe étude et de 118,3 (DS 1,0) dans le groupe contrôle (P < 0,001). L'index général intellectuel en âge préscolaire était de 112.6 (DS 3.7), respectivement de 119.3 (DS 3.1 ), sans différence significative entre les deux groupes. A 18 mois, les taux de handicaps majeurs et mineurs dans les groupes études et contrôle étaient de 6% et 3%. Dans la littérature, des taux entre 0% et 33% ont été décrits. A cet âge, il y avait une différence significative pour tous les scores du test de Griffiths, mëme en tenant compte du status socio-économique de la famille. Ceci suggère un léger retard du développement global et non une altération spécifique. Ces différences n'étaient plus significatives en âge préscolaire, suggérant un rattrapage développemental. Le taux de handicaps majeurs en âge préscolaire pour le groupe étude était de 11.5%, sans aucune infirmité motrice cérébrale. Ces résultats correspondent à ceux d'études de suivi après d'autres traitements jusqu'à l'âge de 24 mois avec des taux variant de 0% à 15%. Le taux de handicaps mineurs était de 26.9% dans le groupe étude et de 26.1% dans le groupe contrôle, sans différence significative entre les deux groupes. L'incidence de handicaps mineurs dans le groupe étude était plutôt élevée en comparaison aux données de la littérature (6 à 22% à 6 ans). Une explication possible est que nous avons considéré des problèmes de langage et de comportement comme handicaps mineurs. Ceci suggère une différence méthodologique et non une plus mauvaise issue dans nos deux groupes. Les évaluations cognitives des enfants des deux groupes se trouvaient dans la norme, ce qui est aussi le cas dans la littérature. En conclusion, cette étude longitudinale non randomisée d'enfants traités avec du MgSO4 seul pour une HTPP sévère ne montre pas de conséquences sur le devenir neuro-développemental à long terme. Cette étude le démontre pour la première fois. Malgré le fait que iN0 soit le traitement actuellement recommandé pour l'HTPP du nopuveau-né, le MgSO4 reste largement utilisé, en particulier dans des pays en voie de développement. L'absence de complications neuro-développementales majeures à long terme permet de considérer l'administration du MgSO4 pour le traitement de l'HTPP du nouveau-né en cas de non réponse ou d'inaccessibilité au iNO.

Hypertension and intra-operative incidents: a multicentre study of 125,000 surgical procedures in Swiss hospitals.

It is debated whether chronic hypertension increases the risk of cardiovascular incidents during anaesthesia. We studied all elective surgical operations performed in adults under general or regional anaesthesia between 2000 and 2004, in 24 hospitals collecting computerised clinical data on all anaesthetics since 1996. The focus was on cardiovascular incidents, though other anaesthesia-related incidents were also evaluated. Among 124,939 interventions, 27,881 (22%) were performed in hypertensive patients. At least one cardiovascular incident occurred in 7549 interventions (6% (95% CI 5.9-6.2%)). The average adjusted odds ratio of cardiovascular risk for chronic hypertension was 1.38 (95% CI 1.27-1.49). However, across hospitals, adjusted odd ratios varied from 0.41 up to 2.25. Hypertension did not increase the risk of other incidents. Hypertensive patients are still at risk of intra-operative cardiovascular incidents, while risk heterogeneity across hospitals, despite taking account of casemix and hospital characteristics, suggests variations in anaesthetic practices.