Statistiques appliquées en chirurgie cardiaque adulte : analyses de survie et applications du “propensity score”

L'objectif principal de ce travail est d’étudier en profondeur certaines techniques biostatistiques avancées en recherche évaluative en chirurgie cardiaque adulte. Les études ont été conçues pour intégrer les concepts d'analyse de survie, analyse de régression avec “propensity score”, et analyse de coûts. Le premier manuscrit évalue la survie après la réparation chirurgicale de la dissection aigüe de l’aorte ascendante. Les analyses statistiques utilisées comprennent : analyses de survie avec régression paramétrique des phases de risque et d'autres méthodes paramétriques (exponentielle, Weibull), semi-paramétriques (Cox) ou non-paramétriques (Kaplan-Meier) ; survie comparée à une cohorte appariée pour l’âge, le sexe et la race utilisant des tables de statistiques de survie gouvernementales ; modèles de régression avec “bootstrapping” et “multinomial logit model”. L'étude a démontrée que la survie s'est améliorée sur 25 ans en lien avec des changements dans les techniques chirurgicales et d’imagerie diagnostique. Le second manuscrit est axé sur les résultats des pontages coronariens isolés chez des patients ayant des antécédents d'intervention coronarienne percutanée. Les analyses statistiques utilisées comprennent : modèles de régression avec “propensity score” ; algorithme complexe d'appariement (1:3) ; analyses statistiques appropriées pour les groupes appariés (différences standardisées, “generalized estimating equations”, modèle de Cox stratifié). L'étude a démontrée que l’intervention coronarienne percutanée subie 14 jours ou plus avant la chirurgie de pontages coronariens n'est pas associée à des résultats négatifs à court ou long terme. Le troisième manuscrit évalue les conséquences financières et les changements démographiques survenant pour un centre hospitalier universitaire suite à la mise en place d'un programme de chirurgie cardiaque satellite. Les analyses statistiques utilisées comprennent : modèles de régression multivariée “two-way” ANOVA (logistique, linéaire ou ordinale) ; “propensity score” ; analyses de coûts avec modèles paramétriques Log-Normal. Des modèles d’analyse de « survie » ont également été explorés, utilisant les «coûts» au lieu du « temps » comme variable dépendante, et ont menés à des conclusions similaires. L'étude a démontrée que, après la mise en place du programme satellite, moins de patients de faible complexité étaient référés de la région du programme satellite au centre hospitalier universitaire, avec une augmentation de la charge de travail infirmier et des coûts.

Role of Nuclear Angiotensin-II Receptor Mediated Signalling in Cardiovascular Remodelling

Le remodelage cardiaque est le processus par lequel la structure ou la fonction cardiaque change en réponse à un déséquilibre pathophysiologique tel qu'une maladie cardiaque, un contexte d'arythmie prolongée ou une modification de l'équilibre hormonal. Le système rénine-angiotensine (SRA) est un système hormonal largement étudié et il est impliqué dans de nombreuses activités associées au remodelage cardiovasculaire. L’existence d'un système circulatoire couplé à un système de tissus locaux est une représentation classique, cependant de nouvelles données suggèrent un SRA indépendant et fonctionnellement actif à l'échelle cellulaire. La compréhension de l'activité intracellulaire du SRA pourrait mener à de nouvelles pistes thérapeutiques qui pourraient prévenir un remodelage cardiovasculaire défavorable. L'objectif de cette thèse était d'élucider le rôle du SRA intracellulaire dans les cellules cardiaques. Récemment, les récepteurs couplés aux protéines G (RCPG), les protéines G et leurs effecteurs ont été détectés sur des membranes intracellulaires, y compris sur la membrane nucléaire, et les concepts de RCPG intracellulaires fonctionnels sont en voie d'être acceptés comme une réalité. Nous avons dès lors fait l'hypothèse que la signalisation du SRA délimitant le noyau était impliquée dans le contrôle de l'expression des gènes cardiaques. Nous avons démontré la présence de récepteurs d'angiotensine de type-1 (AT1R) et de type-2 (AT2R) nucléaires dans les cardiomyocytes ventriculaires adultes et dans une fraction nucléaire purifiée de tissu cardiaque. Des quantités d'Ang II ont été détectées dans du lysat de cardiomyocytes et des microinjections d'Ang-II-FITC ont donné lieu à des liaisons préférentielles aux sites nucléaires. L'analyse transcriptionnelle prouve que la synthèse d'ARN de novo dans des noyaux isolés stimulés à l'Ang-II, et l'expression des ARNm de NF-κB étaient beaucoup plus importants lorsque les noyaux étaient exposés à de l'Ang II par rapport aux cardiomyocytes intacts. La stimulation des AT1R nucléaires a engendré une mobilisation de Ca2+ via les récepteurs de l'inositol trisphosphate (IP3R), et le blocage des IP3R a diminué la réponse transcriptionnelle. Les méthodes disponibles actuellement pour l'étude de la signalisation intracrine sont limitées aux méthodes indirectes. L'un des objectifs de cette thèse était de synthétiser et caractériser des analogues d'Ang-II cellule-perméants afin d’étudier spécifiquement dans les cellules intactes l'activité intracellulaire du SRA. Nous avons synthétisé et caractérisé pharmacologiquement des analogues photosensibles Ang-II encapsulée en incorporant un groupement 4,5-diméthoxy-2-nitrobenzyl (DMNB) photoclivable sur les sites actifs identifiés du peptide. Chacun des trois analogues d'Ang II encapsulée synthétisés et purifiés: [Tyr(DMNB)4]Ang-II, Ang-II-ODMNB et [Tyr(DMNB)4]Ang-II-ODMNB a montré une réduction par un facteur deux ou trois de l'affinité de liaison envers AT1R et AT2R dans les dosages par liaison compétitive et une activité réduite dans la contraction de l'aorte thoracique. La photostimulation de [Tyr(DMNB)4]Ang-II dans des cellules HEK a augmenté la phosphorylation d'ERK1/2 (via AT1R) et la production de cGMP (via AT2R) alors que dans les cardiomyocytes isolés elle générait une augmentation de Ca2+ nucléoplasmique et initiait la synthèse d'ARNr 18S et d'ARNm du NF-κB. Les fibroblastes sont les principaux générateurs de remodelage cardiaque structurel, et les fibroblastes auriculaires sont plus réactifs aux stimuli profibrotiques que les fibroblastes ventriculaires. Nous avons émis l'hypothèse que l’Ang-II intracellulaire et l'activation des AT1R et AT2R nucléaires associés contrôlaient les profils d'expression des gènes des fibroblastes via des systèmes de signalisation distincts et de ce fait jouaient un rôle majeur dans le développement de la fibrose cardiaque. Nous avons remarqué que les fibroblastes auriculaires expriment l’AT1R et l’AT2R nucléaire et l'Ang-II au niveau intracellulaire. L’expression d'AT1R nucléaire a été régulés positivement dans les cas d’insuffisance cardiaque (IC), tandis que l'AT2R nucléaire a été glycosylé post-traductionnellement. La machinerie protéique des protéines G, y compris Gαq/11, Gαi/3, et Gβ, a été observée dans des noyaux isolés de fibroblastes. AT1R et AT2R régulent l'initiation de la transcription du fibroblaste via les voies de transduction de signal d'IP3R et du NO. La photostimulation de [Tyr(DMNB)4]Ang-II dans une culture de fibroblastes auriculaire déclenche la libération de Ca2+ nucléoplasmique, la prolifération, et la synthèse et sécrétion de collagène qui ne sont pas inhibées par les bloqueurs d'AT1R et/ou AT2R extracellulaires.

Nuevos factores de riesgo para enfermedad cardiovascular en artritis reumatoide

Introducción: Dado que la enfermedad cardiovascular (ECV) es la causa más común de mortalidad en pacientes con artritis reumatoide (AR), el objetivo fue determinar los factores asociados a esta complicación en una serie amplia de pacientes colombianos. Adicionalmente, se efectuó una revisión sistemática de la literatura para abordar el estado del arte sobre los factores de riesgo no tradicionales para la ECV en AR. Métodos: Estudio analítico, de tipo corte transversal en el que 800 pacientes colombianos con AR se evaluaron teniendo en cuenta variables asociadas a ECV. Se siguieron las pautas de los elementos de Información Preferidos para Revisiones Sistemáticas y Meta-análisis (PRISMA). Resultados: Colesterol ≥200 mg/dL (OR 3.44; IC 95% 2.21-5.38; p<0.0001), índice de masa corporal anormal (OR 1.70; IC 95% 1.12-2.58; p=0.011), fueron factores de riesgo tradicionales significativamente asociados con ECV en estos pacientes. Como factores no tradicionales de riesgo, autoinmunidad familiar (OR 2.03; IC 95% 1.13-3.65; p=0.017), más de 10 años de enfermedad (OR 2.12; IC 95% 1.36-3.29; p=0.001), trabajadores en las tareas del hogar (OR 2.29; IC 95% 1.45-3.61; p<0.0001), uso de esteroides sistémicos (OR 2.51; IC 95% 1.18-5.37; p=0.017) se asociaron con ECV en nuestra población. A través de la revisión sistemática varios factores y resultados relacionados con las ECV fueron confirmados e identificados. Conclusiones: Los factores de riesgo tradicionales no explican completamente las altas tasas de ECV en los pacientes con AR. Así, factores de riesgo no tradicionales, relacionados con autoinmunidad se reconocen ahora y actúan sinérgicamente, como predictores de esta comorbilidad.

Prevalencia de factores de riesgo cardiovascular en niños de 3 a 17 años

Introducción: Los factores de riesgo de la enfermedad cardiovascular (FRECV) pueden estar presentes desde la infancia y predicen la enfermedad cardiovascular del adulto. Objetivo: Evaluar la prevalencia de FRECV en niños de 3 a 17 años hijos de Enfermeras de la Fundación CardioInfantil - Instituto de cardiología (FCI). Métodos: Estudio de corte transversal analítico. Resultados: 118 niños, edad promedio 7,4 años, desviación estándar 3,86, la mayoría eutróficos 72,0%. Presentaron FRECV como malos hábitos alimenticios 89,0%, sedentarismo 78,8%, exposición a tabaco 19,5%, historia familiar de riesgo cardiovascular 16,1%, sobrepeso 15,3% y obesidad 12,7%. No se encontraron diferencias entre factores de riesgo entre niños y niñas.El sedentarismo en niños con sobrepeso u obesidad fue del 90,9% y en niños eutróficos del 36,5%. Los malos hábitos alimentarios en niños con sobrepeso u obesidad fueron 84,8% y en niños eutróficos 42,4%. Los adolescentes presentaron una mayor exposición a tabaco en comparación con los preescolares y escolares, al igual que una mayor proporción de malos hábitos alimenticios en comparación con ambos grupos. De la totalidad de la población de estudio, el 97,5% presentó al menos un FRECV, y el 42,4% 3 o más FRECV. La presencia de ≥3 FRECV fue mayor en obesos al compararlos con los niños en sobrepeso y eutróficos. Conclusiones: Los resultados del estudio indican que los niños de 3 a 17 años evaluados presentan una alta carga de FRECV, en especial en aquellos con sobrepeso y obesidad.

Eficacia de los inhibidores selectivos de recaptación de serotonina en síntomas no cognitivos del alzhéimer: revisión sistemática

Introducción: El Alzhéimer tiene una prevalencia de 1,6% en las personas mayores de 65 años. Se caracteriza por la pérdida de memoria y otras funciones cognoscitivas, pero más del 70% de los afectados presentan síntomas no cognitivos entre los que se encuentran alteraciones del afecto, comportamiento y psicosis. Estos síntomas están asociados a mayores tasas de institucionalización, morbilidad y mortalidad. Métodos: Revisión sistemática de la literatura de artículos que proporcionaron información sobre la eficacia de los inhibidores selectivos de recaptación de serotonina en síntomas no cognitivos del Alzhéimer. Resultados: La búsqueda inicial arrojó un total de 495 resultados, 64 artículos fueron preseleccionados y 7 se incluyeron en la revisión; éstos se clasificaron como nivel de evidencia Ib; citalopram mostró ser más eficaz que el placebo y similar a antipsicóticos para síntomas comportamentales y psicóticos asociados al Alzhéimer con un perfil de efectos adversos más tolerable; sertralina no mostró eficacia en depresión y sí una mayor incidencia de efectos adversos con respecto al placebo. Discusión: Se obtuvieron resultados favorables en síntomas comportamentales y psicóticos pero no en afectivos. Las diferencias metodológicas de los estudios le dan complejidad a la interpretación de los resultados. Conclusión: La evidencia sugiere que el tratamiento con citalopram es eficaz en síntomas comportamentales y psicóticos asociados al Alzhéimer; para el tratamiento de la depresión asociado a esta demencia aún no existe un antidepresivo que pueda considerarse de elección.

Uso de la matriz extracelular como material para ingeniería de tejidos

Introducción: La evaluación de injertos vasculares de submucosa de intestino delgado para la regeneración de vasos sanguíneos ha producido una permeabilidad variable (0-100%) que ha sido concurrente con la variabilidad en las técnicas de fabricación. Metodología: Investigamos los efectos de fabricación en permeabilidad y regeneración en un diseño experimental de 22factorial que combino: 1) preservación (P) o remoción (R) de la capa estratum compactum del intestino, y 2) deshidratada (D) o hidratada (H), dentro de cuatro grupos de estudio (PD, RD, PH, RH). Los injertos fueron implantados en las Arterias Carótidas de porcinos (ID 4.5mm, N=4, 7d). Permeabilidad, trombogenicidad, reacción inflamatoria, vascularización, infiltración de fibroblastos, perfil de polarización de macrófagos y fuerza tensil biaxial fueron evaluadas. Resultados: Todos los injertos PD permanecieron permeables (4/4), pero tuvieron escasa vascularización e infiltración de fibroblastos. El grupo RD permaneció permeable (4/4), presentó una extensa vascularización e infiltración de fibroblastos, y el mayor número del fenotipo de macrófagos (M2) asociado a regeneración. El grupo RH presentó menor permeabilidad (3/4), una extensa vascularización e infiltración de fibroblastos, y un perfil dominante de M2. El grupo PH presentó el menor grado de permeabilidad, y a pesar de mayor infiltración celular que PD, exhibió un fenotipo de macrófagos dominante adverso. La elasticidad de los injertos R evolucionó de una manera similar a las Carótidas nativas (particularmente RD, mientras que los injertos P mantuvieron su rigidez inicial. Discusión: Concluimos que los parámetros de fabricación afectan drásticamente los resultados, siendo los injertos RD los que arrojaron mejores resultados.

Functional food, blood lipids and cardiovascular disease. Part 1: probiotics

For the past 20 years, the focuses of public health strategies for reducing the risk of cardiovascular disease (CVD) have been aimed at lowering cholesterol levels. However recent findings have highlighted not only cholesterol but also triacylglycerol as a lipid risk factor for CVD. Dietary strategies which are able to reduce these circulating lipid levels, but which are able to offer long-term efficacy comparable with effective drug treatments, are currently being sought. One dietary strategy that has been proposed to benefit the lipid profile involves the supplementation of the diet with probiotics (Part 1), prebiotics and synbiotics (Part 2), which are mechanisms to improve the health of the host by supplementation and/or fortification of certain health promoting gut bacteria. Probiotics in the form of fermented milk products have been shown to have cholesterol-lowering properties, whereas non-digestible fermentable prebiotics have been shown to reduce triacylglycerol levels in animal studies. However in humans studies, there have been inconsistent findings with respect to changes in lipid levels with both prebiotics and probiotics although on the whole there have been favourable outcomes.

Functional food, blood lipids and cardiovascular disease. Part 2: prebiotics and synbiotics

For the past 20 years, the focuses of public health strategies for reducing the risk of cardiovascular disease (CVD) have been aimed at lowering cholesterol levels. However, recent findings have highlighted not only cholesterol but also triacylglycerol as a lipid risk factor for CVD. Dietary strategies which are able to reduce these Circulating lipid levels, but which are able to offer longterm efficacy comparable with effective drug treatments, are currently being sought. One dietary strategy that has been proposed to benefit the lipid profile involves the supplementation of the diet with probiotics (Part 1) prebiotics and synbiotics (Part 2), which are mechanisms to improve the health of the host by supplementation and/or fortification of certain health promoting gut bacteria. Probiotics in the form of fermented milk products have been shown to have cholesterol-lowering properties, whereas non-digestible fermentable prebiotics have been shown to reduce triacylglycerol levels in animal studies, However, in human studies, there have been inconsistent findings with respect to changes in lipid levels with both prebiotics and probiotics although on the whole there have been favourable outcomes.

Omega-3 polyunsaturated fatty acids and human health outcomes

Current intakes of very long chain omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DNA) are low in most individuals living in Western countries. A good natural source of these fatty acids is seafood, especially oily fish. Fish oil capsules contain these fatty acids too. Very long chain w-3 fatty acids are readily incorporated from capsules into transport, functional, and storage pools. This incorporation is dose-dependent and follows a kinetic pattern that is characteristic for each pool. At sufficient levels of incorporation, EPA and DHA influence the physical nature of cell membranes and membrane protein-mediated responses, eicosanoid generation, cell signaling and gene expression in many different cell types. Through these mechanisms, EPA and DHA influence cell and tissue physiology, and the way cells and tissues respond to external signals. In most cases, the effects seen are compatible with improvements in disease biomarker profiles or in health-related outcomes. As a result, very long chain omega-3 fatty acids play a role in achieving optimal health and in protection against disease. Long chain omega-3 fatty acids protect against cardiovascular morbidity and mortality, and might be beneficial in rheumatoid arthritis, inflammatory bowel diseases, childhood learning, and behavior, and adult psychiatric and neurodegenerative illnesses. DHA has an important structural role in the eye and brain, and its supply early in life is known to be of vital importance. On the basis of the recognized health improvements brought about by long chain omega-3 fatty acids, recommendations have been made to increase their intake. (C) 2009 International Union of Biochemistry and Molecular Biology, Inc. Volume 35, Number 3, May/June 2009, Pages 266-272. E-mail: pcc@soton.ac.uk

Maternal depression and psychiatric outcomes in adolescent offspring: a13-year longitudinal study

Background: Maternal postnatal depression (PND) has been associated with adverse outcomes in young children, but an association with longer-term psychiatric disorder has not been demonstrated. We present the preliminary findings of a 13-year longitudinal study. Methods: In the course of a prospective longitudinal study, we examined DSM-IV Axis I disorders in 13-year-old adolescents who had (n=53) or had not (n=41) been exposed to maternal PND. We also detailed the occurrence of depression in mothers throughout the 13-year follow-up period. Results: Maternal PND was associated with higher rates of affective disorders in adolescent offspring. However, mothers who developed PND were also substantially more likely than those who did not to experience depression subsequently, a fact that contributed to the development of depressive disorder in offspring. Maternal PND was associated with increased risk for depression in adolescent offspring only if there had also been later episodes of maternal depression. In contrast, anxiety disorders in offspring were elevated in the maternal PND group regardless of the occurrence of subsequent maternal depression. Limitations: Due to the modest sample size and consequently limited power, findings must be regarded as preliminary. Conclusions: The particular association between early maternal depression and anxiety disorders in offspring was consistent with theories that emphasise the primacy of early environmental exposures. This position was not supported with respect to offspring depressive disorder, where overall duration of maternal depression was a significant factor. PND was associated with recurrent episodes of depression in the majority of cases, underlining the need for monitoring of this population beyond the postnatal period. (c) 2006 Elsevier B.V. All rights reserved.

Effect of changing the amount and type of fat and carbohydrate on insulin sensitivity and cardiovascular risk: the RISCK (Reading, Imperial, Surrey, Cambridge, and Kings) trial

Background: Insulin sensitivity (Si) is improved by weight loss and exercise, but the effects of the replacement of saturated fatty acids (SFAs) with monounsaturated fatty acids (MUFAs) or carbohydrates of high glycemic index (HGI) or low glycemic index (LGI) are uncertain. Objective: We conducted a dietary intervention trial to study these effects in participants at risk of developing metabolic syndrome. Design: We conducted a 5-center, parallel design, randomized controlled trial [RISCK (Reading, Imperial, Surrey, Cambridge, and Kings)]. The primary and secondary outcomes were changes in Si (measured by using an intravenous glucose tolerance test) and cardiovascular risk factors. Measurements were made after 4 wk of a high-SFA and HGI (HS/HGI) diet and after a 24-wk intervention with HS/HGI (reference), high-MUFA and HGI (HM/HGI), HM and LGI (HM/LGI), low-fat and HGI (LF/HGI), and LF and LGI (LF/LGI) diets. Results: We analyzed data for 548 of 720 participants who were randomly assigned to treatment. The median Si was 2.7 × 10−4 mL · μU−1 · min−1 (interquartile range: 2.0, 4.2 × 10−4 mL · μU−1 · min−1), and unadjusted mean percentage changes (95% CIs) after 24 wk treatment (P = 0.13) were as follows: for the HS/HGI group, −4% (−12.7%, 5.3%); for the HM/HGI group, 2.1% (−5.8%, 10.7%); for the HM/LGI group, −3.5% (−10.6%, 4.3%); for the LF/HGI group, −8.6% (−15.4%, −1.1%); and for the LF/LGI group, 9.9% (2.4%, 18.0%). Total cholesterol (TC), LDL cholesterol, and apolipoprotein B concentrations decreased with SFA reduction. Decreases in TC and LDL-cholesterol concentrations were greater with LGI. Fat reduction lowered HDL cholesterol and apolipoprotein A1 and B concentrations. Conclusions: This study did not support the hypothesis that isoenergetic replacement of SFAs with MUFAs or carbohydrates has a favorable effect on Si. Lowering GI enhanced reductions in TC and LDL-cholesterol concentrations in subjects, with tentative evidence of improvements in Si in the LF-treatment group. This trial was registered at clinicaltrials.gov as ISRCTN29111298.

Dietary patterns and cardiovascular disease

Despite strong prospective epidemiology and mechanistic evidence for the benefits of certain micronutrients in preventing CVD, neutral and negative outcomes from secondary intervention trials have undermined the efficacy of supplemental nutrition in preventing CVD. In contrast, evidence for the positive impact of specific diets in CVD prevention, such as the Dietary Approaches to Stop Hypertension (DASH) diet, has focused attention on the potential benefits of whole diets and specific dietary patterns. These patterns have been scored on the basis of current guidelines for the prevention of CVD, to provide a quantitative evaluation of the relationship between diet and disease. Using this approach, large prospective studies have reported reductions in CVD risk ranging from 10 to 60% in groups whose diets can be variously classified as 'Healthy', 'Prudent', Mediterranean' or 'DASH compliant'. Evaluation of the relationship between dietary score and risk biomarkers has also been informative with respect to underlying mechanisms. However, although this analysis may appear to validate whole-diet approaches to disease prevention, it must be remembered that the classification of dietary scores is based on current understanding of diet-disease relationships, which may be incomplete or erroneous. Of particular concern is the limited number of high-quality intervention studies of whole diets, which include disease endpoints as the primary outcome. The aims of this review are to highlight the limitations of dietary guidelines based on nutrient-specific data, and the persuasive evidence for the benefits of whole dietary patterns on CVD risk. It also makes a plea for more randomised controlled trials, which are designed to support food and whole dietary-based approaches for preventing CVD.

Crossover study of diets enriched with virgin olive oil, walnuts or almonds. Effects on lipids and other cardiovascular risk markers

Background and aims: Virgin olive oil (VOO) and nuts are basic components of the Mediterranean diet, a heart-healthy dietary pattern. Nuts have well known cholesterol lowering effects, while evidence is unclear for VOO. We designed a study in hypercholesterolemic patients to assess the effects on serum lipids and other intermediate markers of cardiovascular risk of replacing 40% of the fat in the background diet with VOO, walnuts or almonds. Methods and Results: After a 4 week run-in period with a healthy diet, eligible candidates were randomized into three diet sequences in a crossover design, with a common background diet enriched with VOO, walnuts or almonds, lasting 4 weeks each. Outcomes were changes of serum lipids and oxidation and inflammation markers, measured by standard methods. Plasma fatty acids were determined by gas chromatography to assess compliance. In 18 participants completing the study (9 women, mean age 56 y, BMI 25.7 kg/m(2)), LDL-cholesterol was reduced from baseline by 7.3%, 10.8% and 13.4% after the VOO, walnut and almond diets, respectively (P = 0.001, Friedman test). Total cholesterol and LDL/HDL ratios decreased in parallel. LDL-cholesterol decreases were greater than predicted from dietary fatty acid and cholesterol exchanges among diets. No changes of other lipid fractions, oxidation analytes or inflammatory biomarkers were observed. Plasma fatty acid changes after each diet sequence supported good compliance.

Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes

AIMS/HYPOTHESIS: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease. METHODS: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used. RESULTS: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality. CONCLUSIONS/INTERPRETATIONS: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.

A comparison between diuretics and angiotensin-receptor blocker agents in patients with stage I hypertension (PREVER-treatment trial): Study protocol for a randomized double-blind controlled trial

Background: Cardiovascular disease is the leading cause of death in Brazil, and hypertension is its major risk factor. The benefit of its drug treatment to prevent major cardiovascular events was consistently demonstrated. Angiotensin-receptor blockers (ARB) have been the preferential drugs in the management of hypertension worldwide, despite the absence of any consistent evidence of advantage over older agents, and the concern that they may be associated with lower renal protection and risk for cancer. Diuretics are as efficacious as other agents, are well tolerated, have longer duration of action and low cost, but have been scarcely compared with ARBs. A study comparing diuretic and ARB is therefore warranted.Methods/design: This is a randomized, double-blind, clinical trial, comparing the association of chlorthalidone and amiloride with losartan as first drug option in patients aged 30 to 70 years, with stage I hypertension. The primary outcomes will be variation of blood pressure by time, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. The study will last 18 months. The sample size will be of 1200 participants for group in order to confer enough power to test for all primary outcomes. The project was approved by the Ethics committee of each participating institution.Discussion: The putative pleiotropic effects of ARB agents, particularly renal protection, have been disputed, and they have been scarcely compared with diuretics in large clinical trials, despite that they have been at least as efficacious as newer agents in managing hypertension. Even if the null hypothesis is not rejected, the information will be useful for health care policy to treat hypertension in Brazil. Clinical trials registration number: ClinicalTrials.gov: NCT00971165. © 2011 Fuchs et al; licensee BioMed Central Ltd.