Jean-Philippe Drouin-Chartier

Systematic Review of the Association between Dairy Product Consumption and Risk of Cardiovascular-Related Clinical Outcomes

The objective of this systematic review was to determine if dairy product consumption is detrimental, neutral, or beneficial to cardiovascular health and if the recommendation to consume reduced-fat as opposed to regular-fat dairy is evidence-based. A systematic review of meta-analyses of prospective population studies associating dairy consumption with cardiovascular disease (CVD), coronary artery disease (CAD), stroke, hypertension, metabolic syndrome (MetS), and type 2 diabetes (T2D) was conducted on the basis of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Quality of evidence was rated by using the Grading of Recommendations Assessment, Development, and Evaluation scale. High-quality evidence supports favorable associations between total dairy intake and hypertension risk and between low-fat dairy and yogurt intake and the risk of T2D. Moderate-quality evidence suggests favorable associations between intakes of total dairy, low-fat dairy, cheese, and fermented dairy and the risk of stroke; intakes of low-fat dairy and milk and the risk of hypertension; total dairy and milk consumption and the risk of MetS; and total dairy and cheese and the risk of T2D. High- to moderate-quality evidence supports neutral associations between the consumption of total dairy, cheese, and yogurt and CVD risk; the consumption of any form of dairy, except for fermented, and CAD risk; the consumption of regular- and high-fat dairy, milk, and yogurt and stroke risk; the consumption of regular- and high-fat dairy, cheese, yogurt, and fermented dairy and hypertension risk; and the consumption of regular- and high-fat dairy, milk, and fermented dairy and T2D risk. Data from this systematic review indicate that the consumption of various forms of dairy products shows either favorable or neutral associations with cardiovascular-related clinical outcomes. The review also emphasizes that further research is urgently needed to compare the impact of low-fat with regular- and high-fat dairy on cardiovascular-related clinical outcomes in light of current recommendations to consume low-fat dairy.

Comprehensive Review of the Impact of Dairy Foods and Dairy Fat on Cardiometabolic Risk

Because regular-fat dairy products are a major source of cholesterol-raising saturated fatty acids (SFAs), current US and Canadian dietary guidelines for cardiovascular health recommend the consumption of low-fat dairy products. Yet, numerous randomized controlled trials (RCTs) have reported rather mixed effects of reduced- and regular-fat dairy consumption on blood lipid concentrations and on many other cardiometabolic disease risk factors, such as blood pressure and inflammation markers. Thus, the focus on low-fat dairy in current dietary guidelines is being challenged, creating confusion within health professional circles and the public. This narrative review provides perspective on the research pertaining to the impact of dairy consumption and dairy fat on traditional and emerging cardiometabolic disease risk factors. This comprehensive assessment of evidence from RCTs suggests that there is no apparent risk of potential harmful effects of dairy consumption, irrespective of the content of dairy fat, on a large array of cardiometabolic variables, including lipid-related risk factors, blood pressure, inflammation, insulin resistance, and vascular function. This suggests that the purported detrimental effects of SFAs on cardiometabolic health may in fact be nullified when they are consumed as part of complex food matrices such as those in cheese and other dairy foods. Thus, the focus on low-fat dairy products in current guidelines apparently is not entirely supported by the existing literature and may need to be revisited on the basis of this evidence. Future studies addressing key research gaps in this area will be extremely informative to better appreciate the impact of dairy food matrices, as well as dairy fat specifically, on cardiometabolic health.

Comparison of Two Low-Density Lipoprotein Apheresis Systems in Patients With Homozygous Familial Hypercholesterolemia

Low‐density lipoprotein (LDL) apheresis (LA) is a reliable method to decrease LDL‐C concentrations and remains the gold standard therapy in homozygous familial hypercholesterolemia (HoFH). The objective of this study was to compare the efficacy of two LA systems [heparin‐induced extracorporeal LDL precipitation (HELP) vs. dextran sulfate adsorption (DS) on the reduction of lipids, inflammatory markers, and adhesion molecules in a sample of genetically defined HoFH subjects (n = 9)]. Fasting blood samples were collected before and after LA. All subjects served as their own control and were first treated with the HELP system then with DS in this single sequence study. Compared with HELP, DS led to significantly greater reductions in total cholesterol (−63.3% vs. −59.9%; P = 0.05), LDL‐C (−70.5% vs. −63.0%; P = 0.02), CRP (−75.3% vs. −48.8%; P < 0.0001), and TNF‐α (−23.7% vs. +14.7%; P = 0.003). Reductions in the plasma levels of PCSK9 (−45.3% vs. −63.4%; P = 0.31), lipoprotein (a) (−70.6% vs. −65.0%; P = 0.30), E‐selectin (−16.6% vs. −18.3%; P = 0.65), ICAM‐1 (−4.0 vs. 5.6%; P = 0.56), and VCAM‐1 (8.3% vs. −1.8%; P = 0.08) were not different between the two systems. For the same volume of filtered plasma (3,000 mL), however, HELP led to greater reductions in plasma apoB (−63.1% vs. −58.3%; P = 0.04), HDL‐C (−20.6% vs. −6.5%; P = 0.003), and PCSK9 (−63.4% vs. −28.5%; P = 0.02) levels. These results suggest that both LA systems are effective in reducing plasma lipids and inflammatory markers in HoFH. Compared with HELP, greater reductions in lipid levels and inflammatory markers were achieved with DS, most likely because this method allows for a larger plasma volume to be filtered. J. Clin. Apheresis 31:359–367, 2016.

Lipid Metabolism and Emerging Targets for Lipid-Lowering Therapy

Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, and dyslipidemia constitutes a major risk factor for CVD and premature atherosclerosis. Therapies to reduce the plasma levels of atherogenic lipoproteins are well established interventions that decrease CVD risk. However, treatment of dyslipidemia with the most widely used lipid-lowering drugs (ie, statins and ezetimibe) often fails to protect a significant proportion of patients from cardiovascular risk. The development of several novel therapies to treat lipid-related disorders and their associated risks is ongoing and includes the following: (1) reducing plasma levels of atherogenic lipoproteins using proprotein convertase subtilisin/kexin type 9 inhibitors, antisense inhibitors of Apolipoprotein (Apo)(a), microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides of ApoB for inhibiting very low-density lipoprotein production, and inhibitors of angiopoietin-like protein 3 or ApoC-III for triglyceride-rich lipoprotein management upstream of low-density lipoprotein production as well as gene replacement therapy to improve low-density lipoprotein and triglyceride-rich lipoprotein clearance; and (2) emerging therapies that target high-density lipoprotein (HDL) and reverse cholesterol transport using cholesteryl ester transfer protein inhibitors, HDL peptide mimetics, and autologous infusion of pre-β HDLs. Clinical trials of several of these emerging therapies are currently being conducted. Despite the potential efficacy of these new therapies in CVD prevention, their costs might limit their use because of limited reimbursement funds. Therefore, the real challenge facing the next generation of lipid-lowering agents will most likely be accessibility, reflecting a new paradigm that applies to almost all emerging therapies for any disease in the era of precision medicine.

The contribution of PCSK9 levels to the phenotypic severity of familial hypercholesterolemia is independent of LDL receptor genotype

UNLABELLED Autosomal dominant familial hypercholesterolemia (FH) is caused by genetic mutations in the LDL receptor (LDLR), its ligand apolipoprotein (apo) B, or proprotein convertase subtilisin/kexin type 9 (PCSK9). Although PCSK9 levels have been shown to correlate with LDL-cholesterol (LDL-C) levels in FH, the extent to which PCSK9 levels modulate the phenotypic severity of this disease independent of LDLR genotype remains to be clarified. OBJECTIVE To assess the relationship between LDLR genotype and the plasma levels of PCSK9, LDL-C, and lipoprotein (a) (Lp(a)) in a large cohort of genetically defined FH heterozygotes (HeFH). METHODS A total of 292 HeFH carrying one of the nine French-Canadian mutations in the LDLR gene were recruited. The cohort included 226 carriers of a negative-receptor (NR) mutation and 66 carriers of a defective-receptor (DR) LDLR gene mutation. Fifty-six control subjects, who were matched with the HeFH subjects based on gender and body mass index, were also recruited. RESULTS PCSK9 levels were higher in the HeFH group than in the control group (317.9±107.1 ng/mL vs. 203.3±59.8 ng/mL; P<0.0001). The strength of the association between PCSK9 and LDL-C levels was similar among controls (r=0.37; P=0.005) and HeFH (r=0.31; P<0.0001). Furthermore, a multiple linear regression analysis revealed that the positive correlation between PCSK9 and LDL-C levels remained significant after adjusting for LDLR genotype in the HeFH group. CONCLUSION These results suggested that the contribution of PCSK9 levels to the phenotypic severity in FH heterozygotes is independent of LDLR genotype.

Substitution of dietary ω-6 polyunsaturated fatty acids for saturated fatty acids decreases LDL apolipoprotein B-100 production rate in men with dyslipidemia associated with insulin resistance: a randomized controlled trial

Background The substitution of omega (ω)-6 (n-6) polyunsaturated fatty acids (PUFAs) for saturated fatty acids (SFAs) is advocated in cardiovascular disease prevention. The impact of this substitution on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains unknown. Objective In men with dyslipidemia and IR, we evaluated the impact of substituting ω-6 PUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo) B-containing lipoproteins and on the intestinal expression of key genes involved in lipoprotein metabolism. Design Dyslipidemic and IR men (n = 36) were recruited for this double-blind, randomized, crossover, controlled trial. Subjects consumed, in a random order, a fully controlled diet rich in SFAs (SFAs: 13.4% of energy; ω-6 PUFAs: 4.0%) and a fully controlled diet rich in ω-6 PUFAs (SFAs: 6.0%; ω-6 PUFAs: 11.3%) for periods of 4 wk, separated by a 4-wk washout period. At the end of each diet, the in vivo kinetics of apoB-containing lipoproteins were measured and the intestinal expression of key genes involved in lipoprotein metabolism was quantified in duodenal biopsies taken from each participant. Results The substitution of ω-6 PUFAs for SFAs had no impact on TRL apoB-48 fractional catabolic rate (Δ = -3.8%, P = 0.7) and production rate (Δ = +1.2%, P = 0.9), although it downregulated the intestinal expression of the microsomal triglyceride transfer protein (Δ = -18.4%, P = 0.006) and apoB (Δ = -16.6%, P = 0.005). The substitution of ω-6 PUFAs for SFAs decreased the LDL apoB-100 pool size (Δ = -7.8%; P = 0.005). This difference was attributed to a reduction in the LDL apoB-100 production rate after the substitution of ω-6 PUFAs for SFAs (Δ = -10.0%; P = 0.003). Conclusions This study demonstrates that the substitution of dietary ω-6 PUFAs for SFAs decreases the production and number of LDL particles in men with dyslipidemia and IR. This trial was registered at clinicaltrials.gov as NCT01934543.

C-reactive protein levels are inversely correlated with the apolipoprotein B-48-containing triglyceride-rich lipoprotein production rate in insulin resistant men

The pro-inflammatory state and elevated plasma levels of post-prandial triglycerides (TG) are associated with increased cardiovascular disease risk. Recent studies suggested that the increase in the production rate of post-prandial lipoproteins observed in patients with insulin resistance (IR) may be caused, at least in part, by the dysregulation of intestinal insulin sensitivity triggered by inflammation. OBJECTIVE The objective of the present study was to evaluate the association between IR, plasma C-reactive protein (CRP) levels and the kinetics of TG-rich lipoprotein (TRL) containing apolipoprotein (apo) B-48 in a large sample of insulin sensitive (IS) and IR men. METHODS The in vivo kinetics of TRL apoB-48 were measured in 151 men following a primed-constant infusion of l-[5,5,5-D3]leucine. IR subjects (n=91) were characterized by fasting TG levels ≥1.5mmol/L and an index of homeostasis model assessment of IR (HOMA-IR)≥2.5 or type 2 diabetes, while IS subjects (n=24) were characterized by an HOMA-IR index <2.5 and TG levels <1.5mmol/L. RESULTS IR subjects had higher TRL apoB-48 production rate (+202%; P<0.0001) and CRP levels (+51%; P=0.01) than IS subjects. TRL apoB-48 production rate and CRP levels were inversely correlated in IR subjects (r=-0.32; P=0.002). IR subjects with CRP levels above the median (2.20mg/L) had lower TRL apoB-48 production rate than IR subjects with CRP levels below the median (Δ=-24%; P<0.05). CONCLUSION Our results confirm that IR is associated with increased TRL apoB-48 secretion and suggest that a higher inflammatory status is associated with decreased TRL apoB-48 secretion among IR subjects.

Differential impact of the cheese matrix on the postprandial lipid response: a randomized, crossover, controlled trial

Background: In a simulated gastrointestinal environment, the cheese matrix modulates dairy fat digestion. However, to our knowledge, the impact of the cheese matrix on postprandial lipemia in humans has not yet been evaluated.Objective: In healthy subjects, we compared the impact of dairy fat provided from firm cheese, soft cream cheese, and butter on the postprandial response at 4 h and on the incremental area under the curve (iAUC) of plasma triglycerides.Design: Forty-three healthy subjects were recruited to this randomized, crossover, controlled trial. In random order at intervals of 14 d and after a 12-h fast, subjects ingested 33 g fat from a firm cheese (young cheddar), a soft cream cheese (cream cheese), or butter (control) incorporated into standardized meals that were matched for macronutrient content. Plasma concentrations of triglycerides were measured immediately before the meal and 2, 4, 6, and 8 h after the meal.Results: Cheddar cheese, cream cheese, and butter induced similar increases in triglyceride concentrations at 4 h (change from baseline: +59%, +59%, and +62%, respectively; P = 0.9). No difference in the triglyceride iAUC0-8 h (P-meal = 0.9) was observed between the 3 meals. However, at 2 h, the triglyceride response caused by the cream cheese (change from baseline: +44%) was significantly greater than that induced by butter (change from baseline: +24%; P = 0.002) and cheddar cheese (change from baseline: +16%; P = 0.0004). At 6 h, the triglyceride response induced by cream cheese was significantly attenuated compared with that induced by cheddar cheese (change from baseline: +14% compared with +42%; P = 0.0004).Conclusion: This study demonstrates that the cheese matrix modulates the impact of dairy fat on postprandial lipemia in healthy subjects. This trial was registered at clinicaltrials.gov as NCT02623790.

The Low-Density Lipoprotein Receptor Genotype Is a Significant Determinant of the Rebound in Low-Density Lipoprotein Cholesterol Concentration After Lipoprotein Apheresis Among Patients With Homozygous Familial Hypercholesterolemia

In homozygous familial hypercholesterolemia (HoFH) caused by mutations in the low-density lipoprotein (LDL) receptor ( LDLR ) gene, patients with 2 receptor-negative mutations have higher cholesterol concentrations and coronary heart disease risk than patients with double receptor-defective mutations.1 Pharmacological treatment is insufficient to achieve an efficient reduction in LDL-cholesterol (C) or lipoprotein (a) (Lp(a)) concentrations in patients with HoFH, and repetitive long-term lipoprotein apheresis (LA) remains the gold-standard therapy. LA induces an acute decrease in LDL-C and Lp(a) concentrations, which is then followed by a rebound in the following days. The rebound after LA constitutes a major determinant of LA efficacy because it directly affects the average concentrations between treatments, considered the best estimate of the physiological effects of long-term LA.2 However, our understanding of the determinants of rebound after treatment in LDL-C and Lp(a) is limited.2 This study aimed to determine the extent to which the LDLR genotype modulates the rebound after LA in LDL-C and Lp(a) concentrations among patients with HoFH. We hypothesized that the rebound in LDL-C and Lp(a) concentrations is greater among patients with receptor-negative HoFH than among patients with receptor-defective HoFH. Data on all consecutive LA treatments performed between August 2008 and February 2016 among patients with HoFH with genetically defined defective/defective LDLR mutations (n=3), negative/negative LDLR mutations (n=8), and defective/negative LDLR mutations (n=4) treated at the CHU de Quebec-Universite Laval were collected. For each patient, the compiled data included: (1) date of LA, (2) cumulative number of LA treatments received, (3) interval between LA treatments, (4) LA system used, (5) volume of filtered plasma per treatment, (6) duration of treatments, (7) lipoprotein concentrations before and after LA, and (8) cumulative interval since the first compiled LA treatment. Data on …

Ezetimibe increases intestinal expression of the LDL receptor gene in dyslipidaemic men with insulin resistance

To gain further insight into intestinal cholesterol homeostasis in dyslipidaemic men with insulin resistance (IR) by examining the impact of treatment with ezetimibe on the expression of key genes involved in cholesterol synthesis and LDL receptor (R)‐mediated uptake of lipoproteins.