Statistical Modelling of Cardiovascular Data. An Introduction to Linear Mixed Models

Most of statistical approaches in cardiovascular research were based on variance analysis (ANOVA). However, most of the time, the assumption that data are independent is violated since several measures are performed on the same subject (repeated measures). In addition, the presence of intra- and inter-observers variability can potentially obscure significant differences. The linear mixed model (LMM) is an extended multivariate linear regression method of analysis that accounts for both fixed and random effects. LMM allows for addressing incomplete design cases. In this paper, LMM was applied to two sets of cardiovascular research data and compared to ANOVA. The first example is an analysis of heart rate in mice after atropine and propranolol injections. LMM shows an important mouse random effects that depends on pharmacological treatment and provides with accurate estimates for each significant experimental factors. When randomly suppressing observations from the data sets (20-30%) the time factor of Anova model becomes non significant while LMM still remains significant. The second example is the analysis of isolated coronary-perfused pressure of transgenic mice hearts. LMM evidenced a significant transgenic effect in both male and female animals, while, with ANOVA, the transgenic effects was limited to male mice only. In both cases, as compared to ANOVA, the LMM separately accounts for fixed and random effects, allowing thus for studying more adequately incomplete designs on repeated measures

The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease

SummaryA high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease

Cardiomyocyte overexpression of neuronal nitric oxide synthase delays transition toward heart failure in response to pressure overload by preserving calcium cycling.

International audienceBACKGROUND: Defects in cardiomyocyte Ca(2+) cycling are a signature feature of heart failure (HF) that occurs in response to sustained hemodynamic overload, and they largely account for contractile dysfunction. Neuronal nitric oxide synthase (NOS1) influences myocyte excitation-contraction coupling through modulation of Ca(2+) cycling, but the potential relevance of this in HF is unknown. METHODS AND RESULTS: We generated a transgenic mouse with conditional, cardiomyocyte-specific NOS1 overexpression (double-transgenic [DT]) and studied cardiac remodeling, myocardial Ca(2+) handling, and contractility in DT and control mice subjected to transverse aortic constriction (TAC). After TAC, control mice developed eccentric hypertrophy with evolution toward HF as revealed by a significantly reduced fractional shortening. In contrast, DT mice developed a greater increase in wall thickness (P<0.0001 versus control+TAC) and less left ventricular dilatation than control+TAC mice (P<0.0001 for both end-systolic and end-diastolic dimensions). Thus, DT mice displayed concentric hypertrophy with fully preserved fractional shortening (43.7+/-0.6% versus 30.3+/-2.6% in control+TAC mice, P<0.05). Isolated cardiomyocytes from DT+TAC mice had greater shortening, intracellular Ca(2+) transients, and sarcoplasmic reticulum Ca(2+) load (P<0.05 versus control+TAC for all parameters). These effects could be explained, at least in part, through modulation of phospholamban phosphorylation status. CONCLUSIONS: Cardiomyocyte NOS1 may be a useful target against cardiac deterioration during chronic pressure-overload-induced HF through modulation of calcium cycling

Red wine polyphenols prevent metabolic and cardiovascular alterations associated with obesity in Zucker fatty rats (Fa/Fa)

Peer reviewedPublisher PD

Homéostasie des espèces oxygénées réactives et physiopathologie de l'hypertrophie/insuffisance cardiaque (focus sur l'isoforme Nox4 de la NADPH oxydase)

L'insuffisance cardiaque est un risque majeur de morbidité et de mortalité dans les pays industrialisés et constitue un problème majeur de santé publique. Ce syndrome est la voie finale de nombreuses maladies cardiaques qui induisent dans un premier temps un remodelage adaptatif du myocarde, l'hypertrophie du ventricule gauche. Il est de plus en plus évident que les espèces oxygénées réactives interviennent dans le développement de l'hypertrophie et de l'insuffisance cardiaque, en impactant sur des voies moléculaires essentielles à la régulation du trophisme des cellules cardiaques ou à leur survie. Le système NADPH Oxidase dédié à la production de ROS, source majoritaire dans le système cardiovasculaire, est particulièrement impliqué dans le processus physiopathologique cardiaque. Nous avons confirmé que l'activité NADPH Oxidase est augmentée par des stress pro-trophiques, tant in vitro qu'in vivo, et que cette augmentation potentialise le développement de l'hypertrophie et de la défaillance cardiaque. Nous avons constaté les effets antioxydants d'un concentré du contenu en polyphénols de vin rouge, le Provinols tm, grâce auxquels nous supposons qu'il provoque l'adaptation bénéfique du coeur, en réponse à la surcharge chronique de pression, dans un modèle de sténose aortique (TAC), chez le rat. L'isoforme Nox4 est majoritairement sollicité par une stimulation pro-trophique, in vitro. L'utilisation de son inhibiteur pharmacologique sélectif, le GKT137831, ne nous a pas permis de faire la démonstration du rôle joué par l'augmentation de son activité de production de ROs, in vivo, dans le modèle chirurgical de TAC, chez le rat ou la souris. Nous restons, à ce jour, dans l'impossibilité de conclure, quant à son rôle délétère ou protecteur, au cours du remodelage morphologique et fonctionnel cardiaque, grâce à cet outil pharmacologique.Left Ventricular Hypertrophy (LVH) and most importantly heart failure are major causes of morbidity and mortality worldwide. Reactive Oxygen Species (ROS) such as anion superoxide (O2-) and H2O2 play an important role in regulating growth and death of cardiac myocytes and the hypertrophic process is mediated, in part, by oxidative stress-modulated signaling pathways. NADPH Oxidases (Nox) isoforms are a major source of ROS and play an important role in cardiovascular pathophysiology. Here, we demonstrate that NADPH Oxidase activity is augmented by hypertrophic stimuli, in vitro and in vivo. The latter is characterized by an increased Nox-dependent ROS production that may potentiate the development of LVH and its progression towards heart failure. Indeed, we suppose that a daily oral administration of Provinols tm, a mix of red wine polyphenols compounds, by limitating ROS production from NADPH Oxidase system, maintains an adaptative LVH and prevents cardiac dysfunction, in a model of pressure- overload induced by Thoracic Aortic Constriction (TAC) in rats. NADPH Oxidase 4 (Nox4) protein is overexpressed and produce more ROS in neonatal cardiomyocytes stimulated by PE, in vitro. Thus, its overactivation significantly enhanced PE-induced hypertrophy in cardiomyocytes, as evaluated by protein neosynthesis and cell area analysis. We have validated the effect of a new pharmacological selective inhibitor of Nox4 activity, GKT137831, on cultured cardiomyocytes. We have also investigated the impact of a daily oral administration of GKT137831 on cardiac remodeling and dysfunction occurred following TAC, in rats and further in mice. However, further investigation is still needed to understand whether Nox4 is beneficial or detrimental for myocardial adaptation to a chronic mechanical stress.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF