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LE Magazine July 2008

Omega-3 Fatty Acids

Long-term fish consumption is associated with protection against arrhythmia in healthy persons in a Mediterranean region—the ATTICA study.

BACKGROUND: Dietary habits have long been associated with many manifestations of cardiovascular disease. OBJECTIVE: We sought to investigate whether a diet enriched with fish and n-3 fatty acid consumption are associated with changes in the potential duration of the electrical action, as represented by the QT duration on a resting electrocardiogram, in a population-based sample of Greek adults. DESIGN: During 2001 and 2002, we randomly enrolled 1514 men (18-87 y old) and 1528 women (18-89 y old) stratified by age and sex distribution (in the 2001 Greek census) from the Attica area, Greece. We studied several demographic, anthropometric, lifestyle, dietary, and bioclinical factors of the participants. Dietary habits (including fish consumption) were evaluated by using a validated food-frequency questionnaire. All subjects underwent electrocardiography with a 12-lead surface, in which, along with several other indexes, QT duration was measured, and the heart rate-corrected QT (QTc) was calculated (corrected by using Bazett’s rate). The tested hypothesis was evaluated through multiple linear regression analysis, after control for physical activity status, sex, age, medication intake, and several other potential confounders. RESULTS: Compared with fish nonconsumers, those who consumed >300 g fish/wk had a mean 13.6% lower QTc (P<0.01). These findings were confirmed after adjustment for age, sex, physical activity status, BMI, smoking habits, intake of nuts, and other confounders. Moreover, compared with fish nonconsumers, those who consumed >or=300 g fish/wk had a 29.2% lower likelihood of having QTc intervals >0.45 s (P=0.03). CONCLUSIONS: Long-term consumption of fish is associated with lower QTc interval in free-eating people without any evidence of cardiovascular disease. Thus, fish intake seems to provide antiarrhythmic protection at a population level.

Am J Clin Nutr. 2007 May;85(5):1385-91

Antiarrhythmic effects of omega-3 fatty acids.

Fish oil, and omega-3 fatty acids in particular, have been found to reduce plasma levels of triglycerides and increase levels of high-density lipoprotein in patients with marked hypertriglyceridemia, and a pharmaceutical-grade preparation has recently received approval from the US Food and Drug Administration to market for this purpose. However, in both bench research studies and clinical trials, evidence for clinically significant antiarrhythmic properties has also been detected in association with omega-3 fatty acid intake. Arguably the most significant finding in this data set was the reduction in the incidence of sudden death in survivors of myocardial infarction in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione trial and the subsequent recommendation for administration of fish oil as part of the postinfarction regimen in Europe. This article reviews in detail the basic and clinical research studies of fish oil as an antiarrhythmic entity, the forms of preparation and/or administration that appear to possess these properties and those that do not, the types of arrhythmias (ventricular ectopy and atrial fibrillation as well as ventricular tachyarrhythmias) that have been beneficially affected by fish oil administration, and the presumed and known mechanisms by which the beneficial actions are exerted.

Am J Cardiol. 2006 Aug 21;98(4A):50i-60i

Safety considerations with omega-3 fatty acid therapy.

It has been suggested that the potential antithrombotic effect of fish oils may theoretically increase the risk for bleeding, which may be a safety concern for individual patients. However, clinical trial evidence has not supported increased bleeding with omega-3 fatty acid intake, even when combined with other agents that might also increase bleeding (such as aspirin and warfarin). Another potential safety concern is the susceptibility of omega-3 fatty acid preparations to undergo oxidation, which contributes to patient intolerance and potential toxicity. Finally, large amounts of fish consumption may result in adverse experiences due to the potential presence of environmental toxins such as mercury, polychlorinated biphenyls, dioxins, and other contaminants. The risks of exposure to environmental toxins and hypervitaminosis with fish consumption are substantially reduced through purification processes used to develop selected concentrated fish oil supplements and prescription preparations. Thus, in choosing which fish oil therapies to recommend, clinicians should be aware of available information to best assess their relative safety, which includes the US Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) advisory statement regarding fish consumption, the meaning of certain labeling (such as “verification” through the US Pharmacopeia) and the differences in FDA regulatory requirements between nonprescription fish oil supplements and prescription fish oil preparations, and how all of this is important to the optimal treatment of patients.

Am J Cardiol. 2007 Mar 19;99(6A):35C-43C

Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery.

BACKGROUND: Post-operative atrial fibrillation is a common complication of cardiac surgery and has been associated with increased incidence of other complications including post-operative stroke, increased hospital length of stay and increased cost of hospitalisation. Prevention of atrial fibrillation is a reasonable clinical goal and, consequently, many randomised trials have evaluated the effectiveness of pharmacological and non-pharmacological interventions. We systematically reviewed the literature and prepared meta-analyses to better understand the role and effects of various prophylactic therapies against post-operative atrial fibrillation. OBJECTIVES: To assess the effects of pharmacological and non-pharmacological interventions for preventing post-cardiac surgery atrial fibrillation. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE and CINAHL from earliest achievable date to June 2003. We hand searched references from reports and earlier reviews. We searched abstract books and CD-ROMs from annual scientific meetings of American College of Cardiology, American Heart Association, North American Society of Pacing and Electrophysiology and European Heart Organization between 1997-2003. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials comparing pharmacological interventions or non-pharmacological interventions with control treatment, placebo or usual care for the prevention of post-operative atrial fibrillation in post-coronary artery bypass grafting or combined CABG and valvular surgery. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Fifty eight studies were included with a total of 8,565 participants. Interventions included were amiodarone, beta blockers, solatol and pacing. Results favoured treatment for post-operative atrial fibrillation. The data for stroke favoured treatment by a non-significant effect size of 0.81, 95% confidence interval 0.51 to 1.28. Similarly, a positive indication for length of stay was derived but it too was not significant with a weighted mean difference of -0.66, 95% confidence interval -0.95 to -0.37. A positive result for cost of hospitalisation in favour of treatment was achieved, but the statistic is not significant due to low power and large standard deviations: a weighted mean difference of -2717, 95% confidence interval 7,518 to 2,084. Beta-blockers had the greatest magnitude of effect across 28 trials (4074 patients) with an odds ratio (random) of 0.35, 95% confidence interval 0.26 to 0.49. Across all treatment, the odds ratio favoured treatment with a ratio (random) of 0.43, 95% confidence interval 0.37 to 0.51. REVIEWERS’ CONCLUSIONS: Intervention is favoured across the three pharmacological interventions studied and the one non-pharmacological intervention, pacing. The length of stay data favoured treatment (-0.66, 95% confidence interval -0.95 to -0.37).

Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003611

Amiodarone prophylaxis for atrial fibrillation of high-risk patients after coronary bypass grafting: a prospective, double-blinded, placebo-controlled, randomized study.

AIMS: Atrial fibrillation (AF) occurs often in patients after coronary artery bypass grafting (CABG) and can result in increased morbidity and mortality. Previous studies using P-wave signal-averaged electrocardiogram (P-SAECG) have shown that patients with a longer filtered P-wave duration (FPD) have a high risk of AF after CABG. We have shown that patients with an FPD > or = 124 ms and a root-mean-square voltage of the last 20 ms of the P-wave 20 < or = 3.7 microV have an increased risk of AF after surgery. Accordingly, the aim of this study was to investigate whether or not prophylactic peri-operative administration of amiodarone could reduce the incidence of AF in this high-risk group undergoing CABG identified by P-SAECG. METHODS AND RESULTS: In this prospective, double-blinded, placebo-controlled, randomized study, 110 patients received either amiodarone (n = 55) or placebo (n = 55). During CABG, two patients of both groups died. Amiodarone was given as 600 mg oral single dose one day before and from days 2 through 7 after surgery. In addition, amiodarone was also administered intravenously during surgery in a 300-mg bolus for 1 h and as a total maintenance dose of 20 mg/kg weight over 24 h on the first day following surgery. The primary endpoint was the occurrence of AF after CABG. The secondary endpoint was the hospitalization length of stay after CABG. The baseline characteristics were similar in both treatment groups. The incidence of post-operative AF was significantly higher in the placebo group compared with the amiodarone group (85 vs. 34% of patients, P < 0.0001). The prophylactic therapy with amiodarone significantly reduced the intensive care (1.8 +/- 1.7 vs. 2.4 +/- 1.5 days, P = 0.001) and hospitalization length of stay (11.3 +/- 3.4 vs. 13.0 +/- 4.3 days, P = 0.03). In the amiodarone group, concentrations of amiodarone and desethylamiodarone differed significantly between patients with AF and sinus rhythm (amiodarone: 0.96 +/- 0.5 vs. 0.62 +/- 0.4 microg/mL, P = 0.02; desethylamiodarone: 0.65 +/- 0.2 vs. 0.48 +/- 0.1 microg/mL, P = 0.04). CONCLUSION: The incidence of post-operative AF among high-risk patients was significantly reduced by a prophylactic amiodarone treatment resulting in a shorter time of intensive care unit and hospital stay. Our data supports the prophylactic use of amiodarone in peri-operative period in patients at high risk for AF after CABG.

Eur Heart J. 2006 Jul;27(13):1584-91

Dietary alpha-linolenic acid intake and risk of sudden cardiac death and coronary heart disease.

BACKGROUND: Alpha-linolenic acid, an intermediate-chain n-3 fatty acid found primarily in plants, may decrease the risk of fatal coronary heart disease (CHD) through a reduction in fatal ventricular arrhythmias and sudden cardiac death (SCD). METHODS AND RESULTS: We prospectively examined the association between dietary intake of alpha-linolenic acid assessed via updated food-frequency questionnaires and the risk of SCD, other fatal CHD, and nonfatal myocardial infarction (MI) among 76,763 women participating in the Nurses’ Health Study who were free from cancer and completed a dietary questionnaire at baseline in 1984. During 18 years of follow-up, we identified 206 SCDs, 641 other CHD deaths, and 1604 nonfatal MIs. After controlling for coronary risk factors and other fatty acids, including long-chain n-3 fatty acids, the intake of alpha-linolenic acid was inversely associated with the risk of SCD (P for trend, 0.02) but not with the risk of other fatal CHD or nonfatal MI. Compared with women in the lowest quintile of alpha-linolenic acid intake, those in the highest 2 quintiles had a 38% to 40% lower SCD risk. This inverse relation with SCD risk was linear and remained significant even among women with high intakes of long-chain n-3 fatty acids. CONCLUSIONS: These prospective data suggest that increasing dietary intake of alpha-linolenic acid may reduce the risk of SCD but not other types of fatal CHD or nonfatal MI in women. The specificity of the association between alpha-linolenic acid and SCD supports the hypothesis that these n-3 fatty acids may have antiarrhythmic properties.

Circulation. 2005 Nov 22;112(21):3232-8

A brief history of sudden cardiac death and its therapy.

At the end of the 19th century, there was both experimental and clinical evidence that coronary artery obstruction causes ventricular fibrillation and sudden death and that fibrillation could be terminated by electric shocks. The dominant figure at that time was McWilliam, who in 1923 complained that “little attention was given to the new view for many years.” This remained so for many decades. It was not until the 1960s that the medical profession became aware of the magnitude of the problem of sudden death and began to install coronary care units where arrhythmias could be monitored and prompt defibrillation could be delivered. This approach was pioneered by Julian in 1961. Milestones that allowed this development were open-chest defibrillation by Beck, closed-chest defibrillation by Zoll, cardiac massage by Kouwenhoven et al., and development of the DC defibrillator by Lown. In 1980, Mirowski et al. implanted the first implantable cardioverter defibrillator (ICD) in a patient. Thereafter, the use of the ICD increased exponentially. Several randomized trials, largely in patients with coronary artery disease and left ventricular dysfunction or in patients with documented lethal arrhythmias, showed beyond doubt that the ICD is superior to antiarrhythmic drug therapy in preventing sudden death, although a number of trials showed no effect. Trials on antiarrhythmic drugs were disappointing. Sodium channel blockers and “pure” potassium channel blockers actually increase mortality, calcium channel blockers have no effect, and, although amiodarone reduces arrhythmic death, it had no effect on total mortality in the 2 largest trials. Only the beta-blockers have been proven to reduce the incidence of sudden death, but their effect appears not to be related to the suppression of arrhythmias but rather to the reduction in sinus rate. Drugs that prevent ischemic events, or lessen their impact, such as anticoagulants, statins, angiotensin-converting enzyme inhibitors, and aldosteron antagonists, all reduce the incidence of sudden death.

Pharmacol Ther. 2003 Oct;100(1):89-99

Dietary fish oil reduces the occurrence of early afterdepolarizations in pig ventricular myocytes.

Fish oil reduces sudden cardiac death in post myocardial infarction patients. Life-threatening arrhythmias in heart failure are associated with repolarization abnormalities leading to EAD(1) formation. We examined the effects of incorporated fish oil omega3-PUFAs(2) on EAD formation in pig myocytes. Pigs were fed a diet rich in fish oil or sunflower oil (control) for 8 weeks. Myocytes were isolated by enzymatic dissociation and patch-clamped. Susceptibility to EAD formation was tested using E4031 (5 microM), a blocker of I(Kr). The fish oil diet in pigs resulted in increased incorporation of omega3-PUFAs in the sarcolemma of the myocytes compared to the control diet and caused a reduced occurrence of E4031-induced EADs in pig myocytes. A shorter action potential, a reduced action potential prolongation in response to E-4031 and a reduced reactivation of I(Ca,L) by omega3-PUFAs may explain the observed reduction in EADs. A diet rich in fish oil protects against EAD formation.

J Mol Cell Cardiol. 2006 Nov;41(5):914-7

The relationship between fish consumption and stroke incidence. The NHANES I Epidemiologic Follow-up Study (National Health and Nutrition Examination Survey).

OBJECTIVE: To assess the level of fish consumption as a risk factor fo r stroke. METHODS: Participants were members of the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study, a longitudinal cohort study of a national sample. Included in this analysis were white and black women and men aged 45 to 74 years when examined in 1971 through 1975 who did not report a history of stroke at that time. Average follow-up for survivors was 12 years (maximum, 16 years). The main outcome measure was incident stroke (fatal and nonfatal). Fish consumption at baseline was obtained from a 3-month food frequency questionnaire. RESULTS: White women aged 45 to 74 years who consumed fish more than once a week had an age-adjusted risk of stroke incidence only about half that of women who never consumed fish. This effect persisted after controlling for multiple stroke risk variables (relative risk, 0.55;95% confidence interval [CI], 0.32 to 0.93). Fish consumption more than once a week compared with never was not associated with age-adjusted stroke risk in white men aged 45 to 74 years (relative risk, 0.85;95%CI,0.49 to 1.46). In black women and men combined aged 45 to 74 years, any fish consumption compared with never was significantly associated with reduced adjusted stroke risk (relative risk, 0.51;95%CI,0.30 to 0.88).

Arch Intern Med. 1996 Mar 11;156(5):537-42

Effects of dietary fish oil supplementation on platelet aggregability and platelet membrane fluidity in normolipemic subjects with and without high plasma Lp(a) concentrations.

The purpose of this study was to compare the relative effect of n-3 fatty acids on plasma lipids and platelet function in normolipemic subjects (n = 8) with plasma Lp(a) levels greater than 30 mg/dl and normolipemic subjects (n = 7) without detectable plasma Lp(a) concentrations. Six weeks of dietary supplementation (3.8 g EPA and 2.9 g DHA/d) significantly reduced (P less than 0.005) plasma TGs in both groups whereas no changes of plasma TC, LDL-C, HDL-C, and Lp(a), respectively, were found. Collagen- or thrombin-stimulated platelet aggregation and collagen- or thrombin-induced TXB2 generation from platelets decreased by approx. 45% in Lp(a)-negative and Lp(a)-positive platelet donors after a 6 week dietary intake. Four more weeks without n-3 supplementation restored the pretreatment values of TGs, platelet aggregability and TXB2 release. The biophysical properties of platelets from normolipemics with and without high plasma Lp(a) concentrations revealed a similar structural order of platelets at 37 degrees C using DPH, TMA-DPH, or 6-AS as fluorescent probes. Also similar temperature-dependent changes in platelet fluidity from 37 degrees C to 17 degrees C were observed in platelet preparations from Lp(a)-positive and Lp(a)-negative subjects. However, no subtle changes in the structural order of platelets due to nutrient intakes were found in all subjects (n = 15, 19-28 yrs) using fluorescence polarization technique. The present data suggest a similar in vitro platelet behaviour from normolipemic subjects with and without high plasma levels of Lp(a) (which is considered a risk for premature atherosclerosis) in contrast to platelet aggregability and platelet fluidity in certain hyperlipidemic stages.

Atherosclerosis. 1991 Jun;88(2-3):193-201

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