Omega-3 3 Fatty Acids & Heart Disease:

Transcription

1 Professor Parveen Yaqoob Omega-3 3 Fatty Acids & Heart Disease: Just Another Fishy Story? University of Reading

2 Distribution of some major diseases in Greenland Eskimos, Disease No. of cases Expected no. of cases Cancer (all forms) Apoplexy Epilepsy 16 8 Peptic ulcer Multiple sclerosis 0 2 Psoriasis 2 40 Bronchial asthma 1 25 Diabetes mellitus 1 9 Acute myocardial infarction 3 40 The Eskimo Diet Incidence of heart disease is 7.5% of predicted Traditional diet is rich in fat Whale and seal meats are eaten almost every day High intake of Omega-3 3 PUFA (> 12% of energy) Intake of n-3 n 3 PUFA (g/day) Eskimo Adult UK EPA 4.6 DPA 2.6 < 0.25 DHA 5.9 Bang et al. (1980) American Journal of Clinical Nutrition 33;

3 Dietary sources of long chain n-3 n 3 PUFA Long chain n-3 n 3 PUFA (EPA, DPA, DHA) found in: oily fish (tuna, herring, mackerel, salmon); fish oils (e.g. cod liver oil). Metabolism of n-6 n 6 and n-3 n 3 PUFA Linoleic acid (18:2n-6) α-linolenic acid (18:3n-3) 3) GLA (18:3n-6) 6-desaturase Elongase 18:4n-3 DGLA (20:3n-6) 5-desaturase Arachidonic acid (20:4n-6) 20:4n-3 EPA (20:5n-3) FOUND IN OILY FISH & FISH OIL DPA (22:5n-3) DHA (22:6n-3)

4 UK Recommendation for n-3 n 3 PUFA Intakes Department of Health, 1994 & Scientific Advisory Committee for Nutrition, 2004: Individuals should consume at least 2 portions of fish per week, one of which should be oily. Current average intakes are 0.3 portions per week and 70% of adults eat no oily fish at all. Other recommendations for n-3 n 3 PUFA Intakes NICE Patients should be advised to eat at least two to four portions of oily fish per week. If they are not achieving this and have had an MI within the past 3 months consider providing at least 1g daily of omega-3 3 acid ethyl esters treatment licensed for secondary prevention post MI for up to 4 years. AHA, US 500mg/day EPA+DHA 1.0g/day EPA+DHA- diagnosed cardiovascular disease

5 Current UK Intakes of EPA and DHA Givens & Gibbs (2006) Euwijk & Vermunt (2007) SACN recommendation NICE recommendation 246 mg/d 244 mg/d 450 mg/d 1000 mg/d Fish Consumption & CHD Mortality: A Meta-Analysis 11 eligible studies including individuals with an average of 11.8 y of follow-up. Fish intake Pooled RR 1-33 times per month 0.89 (95% CI 0.79 to 1.01) Once per week 0.85 (95% CI 0.76 to 0.96) 2-44 times per week 0.77 (95% CI 0.66 to 0.89) 5 or more times per week 0.62 (95% CI 0.46 to 0.82) Conclusion: Each 20 g/d increase in fish intake was related to a 7% lower risk of CHD mortality (P=0.03). He et al., (2004) Circulation 109;

6 Intervention- The DART Study 2033 men aged <70y who had suffered an MI Advised to eat oily fish or take fish oil supplements (3 x 0.5g/d) vs no advice CV events and mortality followed for 2y % survivors Oily fish No advice 29% reduction in mortality 16% reduction in CV death Time Burr et al. (1989) Lancet ii, Intervention- The GISSI Study 11,324 men who had suffered MI in the previous 3 months Fish oil vs no treatment (1g n-3 n 3 PUFA/d) Follow-up for 2y Relative risk in fish oil group Death, non-fatal MI, stroke 0.90 CV death, non-fatal MI, stroke 0.85 GISSI Prevenzione Investigators (1999) Lancet 354,

7 N-3 3 PUFA benefit CVD outcomes: systematic review Included 14 RCTs, 25 prospective cohort studies and 7 case- control studies of fish oil supplements or diets high in n-3 n 3 PUFA Evidence suggests that increased consumption of n-3 n 3 PUFA reduces the rates of all-cause mortality, cardiac and sudden death, and possibly stroke. However, a-linolenic a acid has no effect. Wang et al., (2006) Am J Clin Nutr 84; Risks and benefits of omega-3 3 fats: systematic review Included 48 RCTs and 41 cohort studies (short and long chain) Results inconsistent No strong evidence of reduced risk of total mortality or cardiovascular events This systematic review includes the angina study by Burr et al., which has been much criticised Hooper et al., (2006) Br Med J 332;

8 The OMEGA Study 3851 patients days after MI undergoing standard therapy (including coronary angiography & other intervention) 1 g/d omega-3 3 ethyl esters (460 mg EPA, 380mg DHA) or 1g olive oil (placebo). Follow-up for 1 yr- all primary and secondary events Results of the OMEGA study No effect on sudden cardiac death. No effect on total mortality. No effect on non-fatal events. Low overall numbers of events. Beneficial effects of n-3 n 3 PUFA overestimated? Power based on 45% risk reduction in absence of CV therapy. A 30% effect would require ~20,000 patients. High levels of fish consumption. Rauch et al., (2010) OMEGA, a randomized, placebo-controlled controlled trial to test the effect of highly purified omega-3 3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 122, Kromhout study MI patients, 60-80y, receiving antihypertensive, anti- thrombotic and lipid modifying therapy. 40 months intervention with margarine: EPA+DHA (400mg/d), ALA (2g/d), EPA+DHA+ALA or placebo. Primary endpoint: rate of major CV events (fatal, non-fatal, CV intervention). Results 671 CV events (13.9%). No effect of any treatment. Low dose. Kromhout et al., (2010) n-3 n 3 Fatty acids and Cardiovascular Events after Myocardial Infarction. New Engl J Med 363, 21.

9 Possible mechanisms for effects of n-3 n 3 PUFA in CHD Blood clotting Blood pressure Blood lipids Arrhythmias Inflammation Eicosanoid synthesis Arachidonic acid Eicosapentaenoic acid Lipoxygenase pathway Cyclooxygenase pathway Leukotrienes (4-series) Leukotrienes (5-series) Inflammation Cell adhesion Chemotaxis Prostaglandins, thromboxanes (2-series) Prostaglandins, thromboxanes (3-series) Inflammation Immunity Blood pressure Pain Blood clotting

10 Bleeding time in Greenland Eskimos Bleeding time (min) Eskimos 8.05 ± 2.56 Danes 4.76 ± 1.39 Significant difference (P<0.01; Wilcoxon signed ranks test) Data are mean ± SD for 21 Eskimos and 21 sex- and age-matched Danes. Dyerberg & Bang (1979) Lancet Oily Fish & Bleeding Time 10 healthy young men (students at Lund University) Increased intake of mackerel & salmon for 11 weeks, providing g/d EPA Bleeding time & platelet aggregation assessed Result Fish diet prolonged bleeding time by 42% and decreased platelet aggregability Thorngren & Gustafson (1981) Lancet ii,

11 Meta-analysis analysis of trials of fish oil & blood pressure 36 controlled trials reviewed incl. 22 double blind Fish oil: - decreased systolic BP by 2.1 mm Hg (95% CI 1.0, 3.2; P < 0.01) - decreased diastolic BP by 1.6 mm Hg (95% CI 1.0, 2.2; P < 0.01) Effects greater in older subjects Effects greater in hypertensive subjects Conclusion increased intake of fish oil may lower BP, especially in older and hypertensive subjects Geleijnse et al. (2002) J. Hypertens. 20, Possible mechanisms for effects of n-3 n 3 PUFA in CHD Blood clotting Blood pressure Blood lipids Arrhythmias Inflammation

12 Blood lipids in Greenland Eskimos Eskimos Danes Cholesterol 2.33 ± ± 0.49 (g/l) Triglycerides 0.57 ± ± 0.62 (g/l) Significant difference (P<0.001) Data are mean ± SD for 61 male Eskimos and sex- and age-matched Danes. Dyerberg & Bang (1971) Lancet Fish oil lowers blood triglycerides, but not blood cholesterol % change TC TAG ** Leigh-Firbank L, et al. British Journal of Nutrition 2002;87: Minihane AM, et al. Arteriosclerosis Thrombosis and Vascular Biology 2000;20:

13 Possible mechanisms for effects of n-3 n 3 PUFA in CHD Blood clotting Blood pressure Blood lipids Arrhythmias Inflammation Intervention- The GISSI Study 11,372 men who had suffered MI in the previous 3 months Fish oil vs placebo (1g n-3 n 3 PUFA/d) Follow-up for 2y Relative risk in fish oil group Death, non-fatal MI, stroke 0.85 CV death, non-fatal MI, stroke 0.80 All fatal events 0.80 CV death 0.70 Sudden death 0.55 GISSI Prevenzione Investigators (1999) Lancet 354,

14 Possible mechanisms for effects of n-3 n 3 PUFA in CHD Blood clotting Blood pressure Blood lipids Arrhythmias Inflammation

15

16 Carotid plaque study 162 patients undergoing carotid endarterectomy Placebo vs sunflower oil vs fish oil 6 g oil/d (0.86g EPA + 0.5g DHA per d) Duration days Thies, Garry, Yaqoob, Rerkasem, Shearman, Gallagher, Calder, Grimble Lancet (2003) 361,

17 n-3 3 fatty acids in carotid plaque lipids Placebo SO Fish oil EPA in PL ** DHA in PL * Significant linear correlation between length of fish oil supplementation and %EPA in plaque Thies, Garry, Yaqoob, Rerkasem, Shearman, Gallagher, Calder, Grimble Lancet (2003) 361, Plaque stability : AHA classification Placebo SO Fish oil Stable plaques ** (Thick uninflamed cap) Unstable plaques ** (Thin, inflamed cap) There was a positive relationship between plaque stability and omega-3 3 content of the plaque i.e. more stable plaques contained more EPA and DHA than unstable plaques Thies, Garry, Yaqoob, Rerkasem, Shearman, Gallagher, Calder, Grimble Lancet (2003) 361,

18 Macrophage infiltration into plaque Placebo SO Fish oil Macrophage staining None Moderate ** Heavy ** There was a negative relationship between macrophage staining and omega-3 3 content of the plaque i.e. plaques with more macrophages contained less EPA and DHA Thies, Garry, Yaqoob, Rerkasem, Shearman, Gallagher, Calder, Grimble Lancet (2003) 361, Estimated doses required for specific effects on CVD risk factors thrombosis (>2g/d) Improves plaque stability (~1.5g/d) blood pressure (>2-3g/d) +ve effects on blood lipids (>2g/d) inflammation/endothelial function/vascular tone > 2g/d

19 Summary Consumption of fish is associated with a lower risk of mortality Fish oil supplementation has been shown to decrease mortality in some secondary prevention trials of cardiovascular disease Omega-3 3 fatty acids could protect against heart disease through effects on blood lipids, blood clotting, arrhythmias & inflammation mation Fish oil supplementation has been shown to improve plaque stability in carotid endarterectomy patients