Unravelling the Impact of Diet on Cardiovascular Health in Heterozygous Familial Hypercholesterolemia: a Metabolomic Approach.

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 whole food plant-based diet low in red and processed meats and high in plant foods, reflecting Canada's Food Guide principles (WFPB diet in further sections), and a standard North American diet (SAD 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 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 WFPB-SAD or SAD-WFPB diet sequence, using a computer-assisted program. The randomization (1:1) will be stratified by sex (female vs male) and LDL-receptor (LDLR) genotype (receptor-negative vs others) in 8 blocks of 8 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 WFPB diet emphasizes low intakes of red and processed meats and high intakes of whole plant-based foods with water as the drink of choice, as per Canada's Food Guide. The SAD 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.

During the diet phases, participants will visit the INAF clinical research unit three times weekly (Monday, Wednesday, Friday) to collect their meals and had the option to eat on-site under 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.