Midway evaluation - Nathalie Puaschitz
Dietary habits and risk factors in patients with coronary artery disease
Background: Cardiovascular disease (CVD) is strongly linked to dietary and lifestyle habits and is currently the number one cause of death globally, and more than one out of five patients with CVD will experience a major cardiovascular event despite lipid lowering and plaque volume reducing therapy. The cholesterol lowering drugs, statins, constitutes the cornerstone of pharmacological CVD prevention. However, there are uncertainties as to whether the clinical effects are only due to the cholesterol lowering itself, or also attributable to other pleiotropic mechanisms of statins. Exploring novel mechanisms of residual CVD risk is therefore of paramount importance to improve risk prediction. Furthermore, elevated circulating levels of the amino acid homocysteine (tHcy) has been associated with increased CVD risk, but the underlying mechanism is not clarified and treatment with tHcy lowering B-vitamins including folate and B12 does not improve risk.
Betaine is the alternative methyldonor in the remethylation of homocysteine to methionine by the enzyme betaine homocysteine methyl transferase (BHMT). BHMT transcription is associated with co-transcription of apolipoprotein B, the main protein in VLDL, and BHMT is inhibited by supplementation with folic acid. Ongoing data in our group further show that a high dosis of statin is also associated with elevated betaine levels. Notably, recent studies indicate that elevated betaine and its metabolite dimethylglycine are associated with incident acute myocardial infarction (AMI) and all-cause death among patients with established CAD, further suggesting that BHMT flux may be important for CVD development. Human studies have demonstrated that whole-grain is a particular rich source of betaine, whereas studies in mice indicate that the flux through BHMT is increased with fat intake. Overall however, there are few studies that have investigated the impact of dietary habits on long-term cardiovascular outcomes in patients with established CAD and who receive modern conventional medication, including lipid modifying therapy.
Aim: The main focus of the project is to investigate the association between dietary intake of fat and fiber, and future risk of coronary events and mortality in patients with CAD. Findings will be evaluated according to treatment with B-vitamins, statin and metabolites of the choline oxidation pathway.
Methods: Prospective cohort study among 3090 patients with CAD who participated in the Western Norway B-vitamin Intervention Trial (WENBIT). This was a randomized, double-blind, placebo-controlled secondary prevention study which investigated the effect of homocysteine lowering B vitamins (0.8 mg folic acid + 0.4 mg vitamin B-12), vitamin B-6 (40 mg), their combination, or placebo on cardiovascular outcomes and all-cause mortality. The majority of participants received lipid lowering statin therapy. Dietary data was collected by a 169-item semi-quantitative food-frequency questionnaire. The cohort has extensive clinical and laboratory data, including blood and urine samples, medical history, anthropometric data, medication, and verified clinical endpoints. Information on incident cardiovascular outcomes and mortality were collected by linking patient data to the Western Norway Cardiovascular Registry, and the Cause of Death Registry at Statistics Norway, respectively.
Results: The cohort includes 2412 (81 % men; average (SD) age 61.7 years. In paper 1, we investigated a possible association between estimated daily intake of SFAs and risk of coronary events and mortality among patients with CAD, using Cox regression analysis. Despite an association between a high SFA intake with overall fat intake and with established CVD risk factors, we found no association with the outcomes. Thus, we hypothesize that overall intake of fat may have a protective in effect in sub-groups.
This will be evaluated in paper II. We will now focus on the association of fat intake with BHMT flux, and therefore also on the possible effect modification by folic acid / B12 and statin treatment. Finally, in paper 3, we will further focus on BHMT, now by evaluating the association of fiber, as a main source of betaine, with the same outcomes.