Bioactive fatty acids and coronary heart disease. Mechanisms and clinical effects of dietary fatty acids
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Background: A high intake of omega-3 (n-3) long-chain polyunsaturated fatty acids (LCPUFAs), which are potential peroxisome proliferator-activated receptor (PPAR) agonists, has been associated with proposed favourable effects related to prevention and treatment of coronary heart disease. The n-3 LCPUFAs eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids are poorly oxidizable and resemble the effects of the modified fatty acid and pan-PPAR agonist tetradecylthioacetic acid (TTA) mainly through PPAR activation.
Aims: Aims were to investigate the dietary intake of n-3 LCPUFAs and risk of future coronary events in patients with coronary artery disease (CAD) and also to try and elucidate the mechanistic effects of PPAR activation using a rodent model.
Subjects and Methods: The human studies were sub-studies of participants from the Western Norway B-Vitamin Intervention Trial, who completed a food frequency questionnaire at baseline, from which daily intake of n-3 LCPUFAs [EPA, docosapentaenoic acid (DPA), and DHA] was estimated based on diet and supplements. A variety of blood markers were also measured. The association between intake of n-3 LCPUFAs and subsequent risk of coronary events was investigated in two papers. In Paper 1 including 2412 patients, the main endpoint was a composite of coronary events. Acute myocardial infarction (AMI) was the outcome in Paper2 including 2378 patients, who were sub-grouped as having no diabetes [glycosylated haemoglobin (HbA1c) <5.7%], pre-diabetes (HbA1c ≥5.7%), or diabetes (previous diabetes, fasting baseline serum glucose ≥7.0, or non-fasting glucose ≥11.1 mmol/L). An animal study was used to investigate the long-term effects of the pan-PPAR agonist TTA and/or high-dose fish oil (FO) on cardiac fatty acid (FA) composition and lipid metabolism (Paper3). Male Wistar rats were given different diets containing 25% (w/v) fat: control diet; TTA diet; FO diet; or diet containing both TTA and FO.
Results: Risk of experiencing an endpoint was evaluated by Cox regression over quartiles (Paper 1) or tertiles (Paper2). Mean ± SD n-3 LCPUFA intake was 0.58 ± 0.29, 0.83 ± 0.30, 1.36 ± 0.44, and 2.64 ± 1.18 g/day in quartiles 1-4, and 0.43 ± 0.24, 1.08 ± 0.37, and 2.38 ± 1.15 g/day in tertiles 1-3, respectively. There was no overall association between dietary n-3 LCPUFA intake and coronary events in the total human cohort (Paper 1). However, a post hoc additive proportional hazards model demonstrated a slightly increased risk of coronary events in participants having an intake of n-3 LCPUFAs <~300 mg/day. Among patients diagnosed with diabetes there was a significantly reduced risk of AMI in those with a high n-3 LCPUFA intake, and there was also a dose-response relation across n-3 LCPUFA tertiles (Paper 2). In contrast, among non-diabetic patients with HbA1c <5.7%, a high n-3 LCPUFA intake tended to be associated with an increased risk of AMI, which was significant for fatal AMI and associated with lower HbA1c. The main limitations of the human studies were their observational design and a limited event rate, particularly in the non-diabetic group. In the rat model (Paper 3), a long-term diet containing TTA or FO induced an increase in cardiac n-3 LCPUFA composition. Several other cardiac FAs, enzymes, and genes were also changed following TTA and/or FO treatment, indicating increased cardiac FA oxidation.
Conclusions:No risk reduction of coronary events or mortality was observed with high intakes of n-3 LCPUFAs in the total population of patients with CAD. However, a high intake of n-3 LCPUFAs was associated with a reduced risk of AMI in diabetic patients, but with an increased risk of fatal AMI in those without diabetes who had HbA1c <5.7%. Long-term treatment with the pan-PPAR agonist TTA, which has its main effect on PPARα, or high-dose FO, having effects on both PPARα and PPARγ, induced marked changes on cardiac FA metabolism.
Consequences:Further studies should investigate whether patients with diabetes may benefit from having a high intake of n-3 LCPUFAs and whether certain patients with normal glucose tolerance may be careful with a very high intake of these FAs. Because excess PPAR stimulation by FAs other than n-3 LCPUFAs may affect the cardiac n-3 LCPUFA composition, the underlying mechanisms should be further evaluated.