Impact of milk consumption on cardiometabolic risk in postmenopausal women with abdominal obesity

Abstract Background The impact of dairy intake on cardiometabolic risk factors associated with metabolic syndrome (MetS) needs further research. Objective To investigate the impact of milk consumption on a wide array of cardiometabolic risk factors associated with MetS (blood lipids, cholesterol homeostasis, glucose homeostasis, systemic inflammation, blood pressure, endothelial function) in postmenopausal women with abdominal obesity. Methods In this randomized, crossover study, 27 women with abdominal obesity consumed two 6-week diets based on the National Cholesterol Education Program (NCEP), one with 3.2 servings/d of 2% fat milk per 2000 kcal (MILK) and one without milk or other dairy (NCEP). The macronutrient composition of both diets was comparable (55% carbohydrates, 15% proteins, 30% fat and 10% saturated fat). Results The MILK diet had no significant effect on LDL-C, triglycerides, LDL size, CRP and cell adhesion molecule concentrations and on indicators of insulin sensitivity. The MILK diet reduced HDL-C, adiponectin, endothelin and fasting glucose levels as well blood pressure (all P ≤ 0.01), but those changes were comparable to those seen with the NCEP milk-free diet (all between-diet P ≥ 0.07). Finally, the MILK diet was associated with lower VLDL apolipoprotein B fractional catabolic rate (−13.4%; P = 0.04) and plasma sterol concentrations (−12.0%; P = 0.04) compared with the control NCEP milk-free diet. Conclusions These data suggest that short-term consumption of low fat milk in the context of a prudent NCEP diet has no favorable nor deleterious effect on cardiometabolic risk factors associated with MetS in postmenopausal women with abdominal obesity

Étude des dyslipoprotéinémies associées à l'hypercholestérolémie familiale et à la résistance à l'insuline : de la physiopathologie à l'approche clinique

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2018L’hypercholestérolémie familiale (HF), causée par une mutation dans le gène du récepteur LDL (RLDL), constitue une des dyslipoprotéinémies primaires les plus fréquentes dans le monde et au Québec. La principale manifestation de cette maladie consiste en des concentrations accrues de cholestérol-LDL (C-LDL). Du côté des dyslipoprotéinémies secondaires, la dyslipoprotéinémie associée à la résistance à l’insuline (RI), caractérisée, entre autres, par une hyperlipidémie postprandiale, est l’une des plus fréquentes. Ces deux anomalies lipidiques induisent le développement de l’athérosclérose et de maladies cardiovasculaires. L’objectif général des travaux présentés dans cette thèse était d’étudier les mécanismes physiopathologiques influençant la sévérité phénotypique des dyslipoprotéinémies associées à l’HF et à la RI ainsi que les effets d’approches cliniques diverses dans la prise en charge de ces maladies lipidiques. Au niveau de la dyslipoprotéinémie associée à l’HF, l’association entre les concentrations plasmatiques de la proprotéine convertase subtilisine/kexine de type 9 (PCSK9) et la sévérité phénotypique de cette dyslipoprotéinémie, telle que mesurée par les concentrations de C-LDL, Lp(a) et d’apolipoprotéine (apo) B (totale et B-48), a d’abord été étudiée. Chez des patients avec une HF hétérozygote, des associations positives entre les concentrations plasmatiques de PCSK9, de CLDL, de Lp(a) et d’apo B totale, mais pas d’apo B-48, ont été observées, et ce, indépendamment du génotype du R-LDL. Par la suite, les mécanismes cardioprotecteurs et les déterminants de l’efficacité de l’aphérèse des lipoprotéines (AL) ont été étudiés dans le traitement de l’HF homozygote. L’AL consiste à délipider le plasma à l’aide d’un système extracorporel. Il a été documenté que l’AL n’a qu’un impact limité sur l’expression sanguine des gènes impliqués dans la santé cardiovasculaire. L’impact différentiel de deux systèmes d’AL sur les concentrations plasmatiques de lipoprotéines contenant l’apo B et autres molécules associées à la santé cardiovasculaire (p.ex. protéines inflammatoires et d’adhésion cellulaire) a aussi été décrit. Enfin, les associations entre les concentrations de triglycérides plasmatiques pré-AL, le génotype du R-LDL et l’efficacité de cette thérapie ont été documentées pour la première fois. Ces nouvelles évidences supportent des traitements d’AL plus intensifs chez les patients avec HF homozygote porteurs de mutations nulles dans le R-LDL et/ou présentant une hypertriglycéridémie. Au niveau de la dyslipoprotéinémie associée à la RI, l’objectif était d’abord de caractériser les altérations dans le métabolisme des lipoprotéines riches en triglycérides (LRTs) d’origine intestinale associées à cette condition. Il a été démontré que les concentrations plasmatiques d’insuline et de glucose sont différemment associées à l’expression intestinale des gènes clés impliqués dans la synthèse de ces lipoprotéines ainsi qu’au taux de sécrétion de ces mêmes lipoprotéines. Les concentrations de protéine C-réactive et de PCSK9 ont aussi été associées au taux de sécrétion de LRTs avec apo B-48 chez des hommes RI. Ces données suggèrent que le métabolisme des LRTs intestinales est altéré par la progression de la RI et/ou le développement de l’insuffisance insulinémique, l’inflammation et la PCSK9. L’impact de l’inhibition de l’absorption intestinale du cholestérol avec l’ezetimibe a ensuite été étudié afin de mieux comprendre les mécanismes hypocholestérolémiants de ce médicament en présence de RI. Il a été démontré que l’ezetimibe augmente l’expression du gène R-LDL, supportant le concept où l’augmentation de la clairance des LDLs induite par l’ezetimibe ne se produit pas qu’au foie, mais aussi à l’intestin. L’impact de deux approches nutritionnelles cliniques différentes sur le métabolisme postprandial des lipoprotéines a finalement été étudié. D’abord, il a été démontré que la substitution des acides gras saturés par des acides gras polyinsaturés oméga-6 ne modifie pas la cinétique postprandiale des LRTs apo B-48, bien qu’elle diminue la concentration plasmatique de LDLs hépatiques chez des hommes avec une RI. Enfin, il a été démontré que la matrice fromagère module l’impact du gras laitier sur la lipémie postprandiale. Une matrice fromagère ferme induit une réponse lipidique postprandiale plus lente qu’une matrice fromagère crémeuse, et ce, indépendamment de la quantité de gras consommé. À l’aide d’une approche translationnelle, de la physiopathologie à l’approche clinique, ce projet de doctorat a permis de développer de nouvelles connaissances sur les dyslipoprotéinémies associées à l’HF et à la RI. Ces travaux permettront de mieux comprendre l’effet de différentes approches médicamenteuses et nutritionnelles dans la prise en charge de ces anomalies lipidiques.Familial hypercholesterolemia (FH), caused by mutation in the LDL-receptor (LDLR) gene, is amongst the most frequent primary dyslipoproteinemias worldwide. Extreme plasma concentrations of LDLcholesterol (LDL-C) is the main clinical feature of this disorder. The dyslipoproteinemia associated with insulin resistance (IR) is amongst the most frequent secondary dyslipidemias and is mainly characterized by postprandial hyperlipidemia. These two dyslipoproteinemias play major role in the pathogenesis of atherosclerosis and cardiovascular diseases. The general objective of this thesis was to study physiopathological mecanisms modulating phenotypic severity of dyslipoproteinemias associated with FH and IR as well as the impact of different clinical approaches in the management of these lipid disorders. With regard to the dyslipoproteinemia associated with FH, the association between plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the phenotypic severity of this dyslipoproteinemia, as evidenced by plasma levels of LDL-C, Lp(a), apo B (total and B-48), was evaluated. In patients with heterozygous FH, positive associations among plasma levels of PCSK9, LDL-C, Lp(a) and total apo B, but not apo B-48, were observed, independent of LDLR genotype. Next, cardioprotective mechanisms and determinants of the efficacy of lipoprotein apheresis (LA) were studied. LA is the gold-standard therapy for homozygous FH as it allows to delipidate plasma using extracorporeal system. Our work demonstrated that LA has only a limited impact on the whole blood expression of genes involved in lipid metabolism and cardiovascular health. We also described the differential impact of two different LA systems on plasma levels of apo B-containing lipoproteins and other molecules involved in cardiovascular health (e.g. inflammatory and adhesion markers). Finally, associations between pre-LA plasma TG levels, the LDLR genotype and LA efficacy was investigated for the first time in homozygous FH (HoFH) patients. These analyses suggest that receptor-negative and/or hypertriglyceridemic HoFH patients may benefit from more frequent LA to reduce their exposure to apoB-containing lipoproteins in comparison with receptor-defective HoFH patients. Regarding the dyslipoproteinemia associated with IR, our first objective was to characterize alterations in intestinal TG-rich lipoprotein (TRL) metabolism associated with this condition. We demonstrated that plasma levels of insulin and glucose are differentially associated with the intestinal expression of key genes involved in TRL synthesis and with the production rate of these lipoproteins. Plasma concentrations of C-reactive protein and PCSK9 were also found to be associated with the apoB-48-containing TRL production rate in IR men. These data suggest that intestinal TRL metabolism is altered by the progression of IR and/or the onset of insulin insufficiency, inflammation and PCSK9. The impact of inhibiting the intestinal cholesterol absorption with ezetimibe was subsequently investigated in order to gain further insight into lipid-lowering mechanisms of this drug in IR state. We demonstrated that ezetimibe increases the intestinal expression of the LDLR gene, supporting the concept that increased clearance of LDLs with ezetimibe occurs not only in the liver, but also in the intestine. The impact of two different dietary interventions on postprandial lipoprotein metabolism was finally studied. We first demonstrated that the substitution of omega-6 polyunsaturated fatty acids for saturated fatty acids has no impact on TRL apo-48 kinetics, but decreases the production rate and the pool size of LDLs apoB-100. We also demonstrated that the cheese matrix modulates the impact of dairy fat on postprandial lipemia. Indeed, firm cheese matrix attenuates postprandial lipid response in comparison with soft cheese matrix, independent of cheese milk-fat content. Using a translational approach, from physiopathology to clinical approach, this thesis allowed to develop new knowledge on dyslipoproteinemias associated with FH and IR. These data will allow us to have a more comprehensive understanding of the impact of different clinical approaches, from diet to drugs, in the management of these lipid disorders

Plasma biomarkers of small intestine adaptations in obesity-related metabolic alterations

Background: Evidence suggests that pathophysiological conditions such as obesity and type 2 diabetes (T2D) are associated with morphologic and metabolic alterations in the small intestinal mucosa. Exploring these alterations generally requires invasive methods, limiting data acquisition to subjects with enteropathies or undergoing bariatric surgery. We aimed to evaluate small intestine epithelial cell homeostasis in a cohort of men covering a wide range of adiposity and glucose homoeostasis statuses. Methods: Plasma levels of citrulline, a biomarker of enterocyte mass, and I-FABP, a biomarker of enterocyte death, were measured by UHPLC‑MS and ELISA in 154 nondiabetic men and 67 men with a T2D diagnosis. Results: Plasma citrulline was signifcantly reduced in men with insulin resistance and T2D compared to insulin sensi‑ tive men. Decreased citrulline levels were, however, not observed in men with uncontrolled metabolic parameters during T2D. Plasma I-FABP was signifcantly higher in men with T2D, especially in presence of uncontrolled glycemic and lipid profle parameters. Integration of both parameters, which estimate enterocyte turnover, was associated with glucose homeostasis as well as with T2D diagnosis. Diferences in biomarkers levels were independent of age and BMI and glucose fltration rates. Conclusions: Our study supports a decreased functional enterocyte mass and an increased enterocyte death rate in presence of metabolic alterations but emphasizes that epithelial cell homeostasis is especially altered in presence of severe insulin resistance and T2D. The marked changes in small intestine cellularity observed in obesity and diabe‑ tes are thus suggested to be part of gut dysfunctions, mainly at an advanced stage of the disease

Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies

Purpose of Review Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. Recent Findings We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3–4% lower risk of diabetes. Yogurt was non-linearly inversely associatedwith diabetes (RR = 0.86, 95%CI: 0.83–0.90 at 80 g/ d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. Summary The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases

Life's Essential 8 in Relation to Cardiovascular Disease and Mortality in Individuals With Diabetes

Background: Evidence regarding the potential health effects of Life's Essential 8 (LE8) score among individuals with type 2 diabetes (T2D) is limited. Objectives: The purpose of this study was to examine the associations of LE8 score with risk of cardiovascular disease (CVD) and mortality among individuals with T2D. Methods: We prospectively followed 19,915 Chinese participants with T2D at baseline or diagnosed during follow-up (Kailuan Study: 2006-2020), who were free of CVD at diagnosis of diabetes. Diet, lifestyle, and health conditions were repeatedly assessed every 2 years. The LE8 score (range 0-100), was calculated based on 8 components: diet quality, physical activity, smoking status, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. We used time-varying cox models to model the associations. Results: During a median follow-up of 11.5 years in participants with T2D, there were 3,295 incident CVD cases and 3,123 deaths. Higher LE8 score was associated with lower risk of CVD incidence and total mortality among participants with diabetes. The multivariate-adjusted HRs for the highest quintile of LE8 score compared with the lowest quintile were 0.56 (95% CI: 0.53-0.59) for CVD, 0.57 (95% CI: 0.53-0.62) for heart disease, 0.53 (95% CI: 0.49-0.57) for stroke, and 0.73 (95% CI: 0.69-0.78) for total mortality (all P trend &lt;0.001). Furthermore, compared with participants with stable or decreased LE8 score after diabetes diagnosis, those with increased LE8 score had 17% to 42% lower risk of CVD, heart disease, stroke, and mortality. Conclusions: A higher LE8 score was associated with a substantially lower risk of CVD incidence and total mortality among adults with T2D.</p

Life's Essential 8 in Relation to Cardiovascular Disease and Mortality in Individuals With Diabetes

Background: Evidence regarding the potential health effects of Life's Essential 8 (LE8) score among individuals with type 2 diabetes (T2D) is limited. Objectives: The purpose of this study was to examine the associations of LE8 score with risk of cardiovascular disease (CVD) and mortality among individuals with T2D. Methods: We prospectively followed 19,915 Chinese participants with T2D at baseline or diagnosed during follow-up (Kailuan Study: 2006-2020), who were free of CVD at diagnosis of diabetes. Diet, lifestyle, and health conditions were repeatedly assessed every 2 years. The LE8 score (range 0-100), was calculated based on 8 components: diet quality, physical activity, smoking status, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. We used time-varying cox models to model the associations. Results: During a median follow-up of 11.5 years in participants with T2D, there were 3,295 incident CVD cases and 3,123 deaths. Higher LE8 score was associated with lower risk of CVD incidence and total mortality among participants with diabetes. The multivariate-adjusted HRs for the highest quintile of LE8 score compared with the lowest quintile were 0.56 (95% CI: 0.53-0.59) for CVD, 0.57 (95% CI: 0.53-0.62) for heart disease, 0.53 (95% CI: 0.49-0.57) for stroke, and 0.73 (95% CI: 0.69-0.78) for total mortality (all P trend &lt;0.001). Furthermore, compared with participants with stable or decreased LE8 score after diabetes diagnosis, those with increased LE8 score had 17% to 42% lower risk of CVD, heart disease, stroke, and mortality. Conclusions: A higher LE8 score was associated with a substantially lower risk of CVD incidence and total mortality among adults with T2D.</p

Correlates of coronary artery calcification prevalence and severity in patients with heterozygous familial hypercholesterolemia

Background Determinants of coronary artery calcification (CAC) prevalence and severity in heterozygous familial hypercholesterolemia (HeFH) remain understudied. The objective of this cross-sectional study was to investigate correlates of CAC in patients with HeFH. Methods A CAC score was calculated by a noncontrast computed tomography scan in women (n = 68) and men (n = 78) with genetically defined HeFH. We classified CAC prevalence and severity using 3 categories: CAC score = 0 Agatston Unit (AU), CAC score = 1-100 AU, and CAC score > 100 AU. Information on potential correlates of CAC including familial and personal health history, cardiovascular risk factors, lipid-lowering medication, and lifestyle habits was collected. Results A total of 95 patients had prevalent CAC. Independent correlates of CAC prevalence and severity included age (odds ratio [OR] per 10 years: 5.06, 95% confidence interval [CI]: 3.19, 7.93, P < 0.0001), family history of premature cardiovascular disease (OR: 3.88, 95% CI: 1.71, 8.81, P = 0.001), male sex (OR: 3.40, 95% CI: 1.49, 7.78, P = 0.004), statin use (OR: 15.5, 95% CI: 1.89, 126, P = 0.01), diet quality assessed with the Alternative Healthy Eating Index score (OR per 1 standard deviation: 0.59, 95% CI: 0.39, 0.90, P = 0.01), ever smoking (OR: 3.06, 95% CI: 1.20, 7.81, P = 0.02), receptor-negative genotype (OR: 3.17, 95% CI: 1.16, 8.66, P = 0.02), lipoprotein(a) year-score (OR per 1 standard deviation of log-transformed year-score: 1.53, 95% CI: 0.99, 2.36, P = 0.05). Conclusions In individuals with HeFH, age, family history of premature cardiovascular disease, sex, statin use, diet quality, smoking status, the LDLR genotype, and lipoprotein(a) concentrations were independently associated with CAC prevalence and severity.Contexte Les déterminants de la prévalence et de la sévérité de la calcification des artères coronaires (CAC) dans l'hypercholestérolémie familiale hétérozygote (HFHe) demeurent peu étudiés. L’objectif de cette étude transversale était d'identifier les corrélats de la CAC chez des patients atteints d’HFHe. Méthodologie Un score calcique coronarien (SCC) a été calculé par un examen de tomodensitométrie sans contraste chez des femmes (n = 68) et des hommes (n = 78) avec HFHe génétiquement définie. Nous avons classé la prévalence et la gravité de la CAC en trois catégories : SCC = 0 unité d’Agatston (UA), SCC = 1 à 100 UA et SCC > 100 UA. Des renseignements ont été recueillis sur des corrélats potentiels de la CAC, dont les antécédents médicaux familiaux et personnels, les facteurs de risque cardiovasculaire, les médicaments hypolipidémiants et les habitudes de vie. Résultats Au total, 95 patients présentaient une CAC. Les corrélats indépendants de la prévalence et de la gravité de la CAC comprenaient l’âge (rapport de cotes [RC] par tranche de 10 ans : 5,06; intervalle de confiance [IC] à 95 % : 3,19 à 7,93; p < 0,0001), des antécédents familiaux de maladie cardiovasculaire précoce (RC : 3,88; IC à 95 % : 1,71 à 8,81; p = 0,001), le sexe masculin (RC : 3,40; IC à 95 % : 1,49 à 7,78; p = 0,004), l’emploi de statines (RC : 15,5; IC à 95 % : 1,89 à 126; p = 0,01), la qualité du régime alimentaire évaluée selon le score AHEI (Alternative Healthy Eating Index) (RC par écart-type : 0,59; IC à 95 % : 0,39 à 0,90; p = 0,01), le tabagisme (RC : 3,06; IC à 95 % : 1,20 à 7,81; p = 0,02), le génotype récepteur-négatif (RC : 3,17; IC à 95 % : 1,16 à 8,66; p = 0,02) et le score lipoprotéine(a)-année (RC par écart-type du score-année transformé en logarithme : 1,53; IC à 95 % : 0,99 à 2,36; p = 0,05). Conclusions Chez les personnes atteintes d’HFHe, l’âge, les antécédents familiaux de maladie cardiovasculaire précoce, le sexe, l’emploi de statines, la qualité du régime alimentaire, le statut de tabagisme, le génotype du LDLR et les concentrations de lipoprotéine(a) ont été associés de façon indépendante à la prévalence et à la gravité de la CAC

Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose-response meta-analysis of prospective cohort studies

With a growing number of prospective cohort studies, an updated dose-response meta-analysis of milk and dairy products with all-cause mortality, coronary heart disease (CHD) or cardiovascular disease (CVD) have been conducted. PubMed, Embase and Scopus were searched for articles published up to September 2016. Random-effect meta-analyses with summarised dose-response data were performed for total (high-fat/low-fat) dairy, milk, fermented dairy, cheese and yogurt. Non-linear associations were investigated using the spine models and heterogeneity by subgroup analyses. A total of 29 cohort studies were available for meta-analysis, with 938,465 participants and 93,158 mortality, 28,419 CHD and 25,416 CVD cases. No associations were found for total (high-fat/low-fat) dairy, and milk with the health outcomes of mortality, CHD or CVD. Inverse associations were found between total fermented dairy (included sour milk products, cheese or yogurt; per 20 g/day) with mortality (RR 0.98, 95% CI 0.97-0.99; I2 = 94.4%) and CVD risk (RR 0.98, 95% CI 0.97-0.99; I2 = 87.5%). Further analyses of individual fermented dairy of cheese and yogurt showed cheese to have a 2% lower risk of CVD (RR 0.98, 95% CI 0.95-1.00; I2 = 82.6%) per 10 g/day, but not yogurt. All of these marginally inverse associations of totally fermented dairy and cheese were attenuated in sensitivity analyses by removing one large Swedish study. This meta-analysis combining data from 29 prospective cohort studies demonstrated neutral associations between dairy products and cardiovascular and all-cause mortality. For future studies it is important to investigate in more detail how dairy products can be replaced by other foods