Unravelling the Impact of Diet on Cardiovascular Health in Heterozygous Familial Hypercholesterolemia.

The investigators will first conduct a fully controlled dietary randomized crossover trial (RCT) including 50 adults with HeFH to investigate the impact of a diet low in red and processed meats and high in plant foods, reflecting Canada's Food Guide, in place of a standard North-American diet on LDL-cholesterol (LDL-C) levels and the plasma metabolome. Such a robust design will also lead to the identification an objective proxy to healthy diet adherence: the metabolomic signature. Secondly, by leveraging a cross-sectional cohort of adults with HeFH, the investigators will evaluate the relationship between the metabolomic signature of the healthy diet and cardiovascular disease risk factors in HeFH.

The research combines a dietary RCT (objectives 1, 2) and a cohort investigation (objective 3), both including adults with genetically-defined HeFH.

The dietary intervention will be undertaken as a crossover RCT at the Institute on nutrition and functional foods (INAF, Laval University) in Quebec City. Participants (men and women with genetically-defined HeFH) will consume in a random order a fully-controlled diet low in red and processed meats and high in plant foods, reflecting Canada's Food Guide principles (CFG diet in further sections), and a standard North American diet (NAD diet; i.e. control diet), reflecting current dietary intakes of French-Canadians, for 4 weeks each, and separated by a 4-week washout period.

Once enrolled, participants will enter a 2- to 4-week run-in period at the beginning of which they will stop taking their lipid-lowering medication for the study duration (16 weeks). Other medications (e.g. anti-hypertensive drugs, oral contraceptives) will be allowed, but doses will have to remain constant during the study. At the end of the run-in, participants will provide a blood sample and complete a self-administered, validated web-based food-frequency questionnaire. Participants will be randomly assigned to either the CFG-NAD or NAD-CFG diet sequence, using a computer-assisted program. The randomization (1:1) will be stratified by sex and LDL-receptor (LDLR) genotype in 5 blocks of 16 subjects. The two diets will be consumed for 4 weeks and separated by a 2- to 4-week washout period. During diet phases, all meals and foods will be provided to ensure optimal diet control using a 7-day cyclic menu. The CFG diet emphasizes low intakes of red and processed meats and high intakes of minimally processed plant foods with water as the drink of choice, as per Canada's Food Guide. The NAD diet reflects current dietary intakes of the French-Canadian adult population in terms of foods, nutrients, and diet quality, as characterized in recent surveys conducted in an age- and a sex-representative sample of adults from the Province of Quebec. An experienced food technician will prepare the diets. Each food and ingredient will be weighed with a precision of ±0.1 g.

On weekdays, subjects will visit INAF Clinical Research Unit to consume their lunch meal under the research coordinator's supervision. At that time, they will also be given their evening meals and the next day's packaged breakfast to take home. Weekend meals will be provided at the Friday visits. A checklist will be provided to all participants to identify the consumed foods.Alcohol, vitamin supplements, and natural health products will not be allowed. Tea and coffee (black) will be allowed (≤2 servings/day without daily fluctuations). Participants will be instructed to maintain their usual physical activity level. At the end of each diet, fasting plasma samples will be collected in ethylenediaminetetraacetic acid (EDTA) tubes. Parts of the samples will be stored at -80℃ for future ancillary analyses. Participants' anthropometry, body composition (DEXA scan), and blood pressure will be measured. To incorporate gender aspects associated with the intervention in knowledge transfer activities, subjects' appreciation of the diets and appetite sensation will be assessed using visual analog scales filled after each meal on day 7 and 28 of each diet.

Objective 1: To investigate the impact of a diet low in red and processed meats and high in plant foods in place of a standard North American diet on LDL-C concentrations - the primary treatment target in HeFH management. This objective will output a convincing demonstration of the cholesterol-lowering effects of diet in adults with HeFH, supporting the effectiveness of dietary interventions in HeFH management. Investigators will compare post-diet LDL-C levels (primary outcome) using mixed models for repeated measures. Secondary outcomes include other atherogenic lipoproteins and lipids (apolipoprotein B, non-HDL-C, total-C, triglycerides, lipoprotein (a)) and other cardiovascular disease risk factors (fasting plasma glucose, fasting insulin, systolic and diastolic blood pressure, FH risk score, 10-year risk of cardiovascular disease). Potential effect modification by key participant characteristics (age, BMI, sex, LDLR genotype, lipoprotein (a) and diet sequence) will also be tested.

Objective 2: To assess the impact of a diet low in red and processed meats and high in plant foods in place of a standard North American diet on the plasma metabolome. This objective serves a dual purpose as it will: 1. inform on the dietary impact on systemic metabolism, beyond its impact on LDL-C levels, further supporting the importance of healthy dietary habits in HeFH; and 2. allow the identification of an unbiased HeFH-specific plasma metabolomic signature of a diet low in red and processed meats and high in plant foods to be used as an objective proxy of diet adherence. To document post-diet differences in plasma metabolome and identify the metabolomic signature of the CFG diet, investigators will derive a reproducible multi-metabolite model discriminating the post-CFG/post-NAD metabolomic profiles.

Objective 3: To evaluate the association between the plasma metabolomic signature of a diet low in red and processed meats and high in plant foods and cardiovascular disease risk. The metabolomic signature will allow to infer how objective adherence to a healthy diet is associated with cardiovascular disease risk in a distinct, large cohort of free-living adults with HeFH. This will provide an innovative demonstration of the role of diet in long-term cardiovascular disease prevention in adults with HeFH, further supporting the importance of a healthy diet in this high-risk population. To evaluate the association between the plasma metabolomic signature of the healthy CFG diet and cardiovascular disease risk in adults with HeFH, investigators will leverage a distinct cross-sectional cohort of adults with HeFH. Upon recruitment, participants underwent a complete clinical assessment and fasting blood samples were collected in EDTA tubes. Investigators will fit and standardize the CFG multi-metabolite model (signature) to the cohort metabolomic data. The relationship between the CFG multi-metabolite model (independent variable) and cardiovascular disease risk factos (plsama lipids, blood pressure) will be assessed using linear regressions.

Results will fill key gaps on the short- and long-term influence of diet on cardiovascular health in HeFH.

Eligibility Criteria:
Inclusion criteria:

* Genetically-defined HeFH
* Premenopausal women with a regular menstrual cycle for \>3 months
* Postmenopausal women (without hormone replacement)

Exclusion criteria:

* Any cardiovascular disease-risk exacerbating conditions (age \>60 years, homozygous FH, personal history of cardiovascular disease, diabetes/anti-diabetic drug use, severe obesity, unstable body weight for \>3 months, uncontrolled hypertension, genetic hypertriglyceridemia),
* Allergies/aversions to components of the experimental diets
* Any condition that would interfere with optimal participation in the intervention.