Fish oils – adjuvant therapy in chronic heart failure?

Abstract

Despite advances in medical management and device therapy, chronic heart failure (CHF) remains a condition of high mortality and poor quality of life. Patients with CHF endure frequent admissions to hospital, with exacerbations of breathlessness or recurrent acute myocardial infarction and have a high incidence of sudden death. A high intake of marine polyunsaturated fatty acids (PUFAs) is associated with lower cardiovascular mortality in the general population, and diabetics, and can reduce cardiovascular deaths post-infarction. Many of the effects of PUFAs could be of benefit in CHF patients. They can improve endothelial function, reduce vascular tone, reduce platelet aggregability, improve myocardial relaxation, stabilize myocardial cells by prolonging the refractory period, and lead to increased appetite and weight gain. They also have potentially important immune-modulating effects, reducing cytokine production and release and altering prostaglandin metabolism. In this review article we discuss the potential benefits of PUFA supplementation in CHF patients using data from clinical trials and in vitro experiments.

Keywords

eicosapentanoic acid docosahexanoic acid arachadonic acid chronic heart failure

Introduction

Heart failure is common [1]. It is a leading cause of death in industrialized countries [2], and the single most common reason for medical admissions to hospital [3]. Recent therapeutic advances have led to benefits on symptoms and prognosis [4].

Recurrent acute myocardial infarction, worsening chronic heart failure (CHF) and sudden (presumed arrhythmic) death are common causes of deterioration leading to hospital admission or death [5]. Conventional therapies are only partially successful leaving patients with a poor prognosis, persistently high readmission rates [6] and reduced quality of life [7].

The association between a diet high in marine polyunsaturated fatty acids (PUFAs) and low cardiovascular mortality in an Eskimo population was first observed by Sinclair in the 1940s [8]. Recent randomized post-infarction studies have suggested that there is a therapeutic benefit of these agents [9, 10] with a significant reduction in cardiovascular death. Subanalysis of the GISSI-prevenzione study, which compared a combination of two fish oils with placebo in more than 11 000 post-infarction patients on otherwise conventional treatment, revealed a significant reduction in sudden death by 3 months (45% over 3 years) and a significant reduction in total mortality by 3 months [11].

Marine PUFAs (fish oils) have also shown promise in patients with cancer cachexia in whom they can reduce markers of inflammation and lead to weight gain [12, 13].

The aim of this article is to discuss the possible benefits of PUFA supplementation in CHF patients using data from clinical trials and in vitro experiments.

Methods

We identified all articles listed on Medline containing the words ‘fish oils', ‘polyunsaturated fatty acids', ‘eicosapentanoic acid' and ‘docosahexanoic acid' and their abbreviations (PUFA, EPA and DHA). We considered the human and animal data for cardiovascular, cellular and metabolic activity. The data of most potential relevance to chronic heart failure was summarized and divided into sections each concentrating on a particular aspect of the syndrome of CHF.

Fatty acid metabolism

A fatty acid is comprised of a long hydrocarbon chain with a single terminal carboxyl group. Fat is mostly comprised of triglycerides, which are combinations of three fatty acids bound together with a glycerol molecule. The particular fatty acids determine whether the fat is solid or liquid at room temperature. Fats are an important source of calories, and their fatty acid constituents are intermediates in the synthesis of phospholipids and eicosanoids (prostaglandins and leukotrienes). Fatty acids may be saturated (no double carbon bonds, such as stearic acid), mono-unsaturated (single carbon double bond, oleic acid) or polyunsaturated (two or more double bonds, linoleic acid). There are several methods used to name these molecules. The commonest fatty acids are recognized by their ‘trivial names'. Fatty acids can also be named by the ‘omega system', which indicates the number of carbon atoms, the number of double bonds, and the position of the double bond closest to the terminal carbon, the carbon atom furthest from the carboxyl group (omega carbon). The major unsaturated fatty acids fall into omega-6 and omega-3, or n-6 and n-3 groups. For example, linoleic acid is a polyunsaturated fatty acid with two double bonds, 18 carbon atoms, and the first double bond is six carbons away from the omega carbon (n-6). Linolenic acid on the other hand is also 18 carbon atoms long, but has three double bonds, and the first double bond is three carbons away from the ‘noncarboxyl end' (n-3). For simplicity, we shall group those of importance by the position of the double bond (n-3 or n-6).

Fatty acids can be broken down or desaturated to other fatty acids by fatty acyl CoA. However, the specificity of distance from the carboxyl group and the requirement for desaturation of at least a 16-carbon chain means that n-3 and n-6 fatty acids cannot be synthesized in humans. This characteristic and their importance as the base agents in metabolism makes them ‘essential' fatty acids and they must therefore be supplied in the diet.

In the typical Western diet, 20–25-fold more n-6 fats than n-3 fats are consumed [14]. Linoleic acid (LA), which is present in high concentrations in soy, corn, safflower and sunflower oils, is the major n-6 fatty acid. There is a low intake of the n-3 homologue of LA, α-linolenic acid (ALA), which is present in leafy green vegetables and in flaxseed and canola oils. Once ingested, these 18-carbon fatty acids are desaturated and elongated to 20-carbon fatty acids. LA is converted to arachidonic acid (AA) and ALA is converted albeit inefficiently to eicosapentanoic acid (EPA). There is little dietary intake of AA and EPA, which are present in meat and fish. The dietary ratios of n-6 and n-3 fatty acids determine the cellular ratios of LA and ALA and also the relative quantities of AA and EPA produced. Inuit Eskimos have a higher relative intake of the two principal n-3 fatty acids EPA and docosahexanoic acid (DHA) due to a higher intake of fish and fish-eating mammals than western populations [15].

The enzymatic conversion of the essential fatty acids occurs by the same pathway (Fig. 1). Due to competition for the cycloxygenase enzyme (COX), the addition of EPA to the cellular environment significantly alters the relative concentrations of the interconversion products, reducing the relative concentrations of the products of AA metabolism [16–20].

Direct cardiovascular and haemodynamic effects of fish oils

Blood pressure

Marine oils in relatively high doses can lower blood pressure in patients with hypertension and hypercholesterolaemia [21–23], probably due to changes in the physiochemical properties of cell membranes and reduced vascular tone [24, 25]. Blood pressure lowering seems to be unrelated to sympathetic activity or vascular reactivity to adrenergic neurotransmitters [26, 27], and is augmented by salt restriction [28], suggesting an effect on the renin–angiotensin system [29]. Recent work in rats has demonstrated altered T-cell calcium signalling as a possible mechanism [30]. Fish oils also increase nitric oxide release in porcine coronary arteries [31].

Lipid profile and ischaemic heart disease

Fish oils have a beneficial effect on lipid profile lowering triglyceride levels [32, 33], and potentiating the effects of statins [34], and although there were some concerns about impaired glycaemic control in diabetics [35–37] this has not been borne out in a large randomized trial [38] or meta-analyses [32, 33]. High fatty fish intake is associated with a reduced mortality from cardiovascular disease [38–44]. The GISSI-prevenzione study examined the benefits of adding DHA and EPA to conventional therapy in 11 323 patients less than 3 months after a myocardial infarction, and demonstrated an important reduction in total mortality [9]. After 4 months of follow-up the active therapy group had a significant reduction in sudden cardiac death, and after 6 months this group had a lower overall cardiac mortality. These are similar results to data from the DART trial where 2033 men patients consumed fatty fish twice a week following an index myocardial infarction [10]. Data looking at the long-term (10-year) benefit of this dietary modification were less impressive, although many patients had not maintained the altered diet [45]. Despite data suggesting reduced mortality, and improvements in vascular tone, and evidence from work in rats suggesting reduced markers of myocardial ischaemia [46], it is unclear whether fish oils improve subjective or objective markers of myocardial ischaemia in patients with stable symptomatic coronary artery disease [47].

Fig. 1

Fatty acid metabolism with the alternative products of n-3 fatty acids. See text for abbreviations.

Cardiac function and ischaemia

Marine oils reduce heart rate [48, 49], and improve diastolic left ventricular function in marmosets and humans [49–51]. This may be due to increased elastic properties of myocardial cells [50] and increased nitric oxide production [52] and release [31].

EPA and DHA but not n-6 fatty acids protect myocardial cells against hypoxia-reoxygenation-induced injury [53], perhaps by inhibiting neutrophil infiltration into infarcted or ischaemic myocardium [54]. Contractile performance of infarcted myocardium can be preserved [55].

Renal function

Fish oil supplementation can increase renal blood flow, reduce renal vascular resistance and increase glomerular filtration rate (GFR) [56] possibly due to altered (prostaglandin E) PG_E metabolism. Fish oils can preserve renal function and lower blood pressure in heart transplant recipients [57].

Anti-inflammatory and immunomodulatory effects

Cytokines

Tumour necrosis factor-alpha (TNFα) is raised in heart failure [58, 59], particularly in those with weight loss [60, 61] and higher levels predict a worse prognosis [62]. It directly stimulates loss of appetite via altered beta-3 and leptin receptor activity [63, 64]. IL-6 is also elevated [59].

Cytokines also stimulate collagenase production [65, 66], increase the expression of adhesion molecules and encourage migration and proliferation of smooth muscle cells in the vascular wall [67].

There is an inverse exponential relation between mono-nuclear cell EPA content and cytokine production. Whether the cellular source of EPA is the diet or endogenous synthesis from dietary ALA, cytokine synthesis decreases as cellular EPA concentrations increase [68, 69]. Increased dietary n-3 fats suppress the production of both TNF-α and IL-1β [68, 70–72]. This is due to an inhibitory effect of EPA on lipopolysaccharidestimulated TNF gene transcription and protein elaboration in monocytes [73]. ALA supplementation can reduce IL-1β and TNF-α production by more than 30% after 4 weeks [68]. EPA and DHA also inhibit IL-6 production in human endothelial cells [74] and reduce the concentrations of TNF-α and IL-1β in the arterial wall [75], thereby potentially reducing smooth muscle cell migration and proliferation.

Prostaglandins

EPA competitively inhibits AA metabolism by competing for COX enzyme sites and can therefore alter the production of inflammatory mediators (Fig. 1) by the preferential formation of prostaglandins of lower pro-inflammatory potency (for example PG_E3) and overall to significantly reduced inflammatory prostaglandin production [76, 77]. EPA also competes with AA for 5-lipoxygenase leading to the formation of leukotriene B5 (LT_B5), which has little inflammatory activity compared with LT_B4 [78, 79]. Thus, increasing dietary n-3 fats shifts the balance of the eicosanoids produced to a less inflammatory mixture. However, the formation of PG_E itself may be anti-inflammatory suggesting that direct competition may not be the only anti-inflammatory mechanism encouraged by fish oils [80].

There are concerns that moderate doses of fish oils > 2 g per day could affect the immune response [81], predominately T-cell responses [82], but even lower doses (150mg DHA+30mg EPA) can modify the cellular immune response in elderly humans [83]. These changes might put elderly patients with concomitant chronic disease at increased risk of acute infections. This matter is not resolved, however, as there are conflicting data about the effects of ALA (a source of DHA and EPA) on cytokine production. One study on healthy elderly human subjects suggests that ALA leads to reduced IL-6 production by stimulated mononuclear cells with no reduction in their production of TNF-α, interleukin (IL) 1beta, IL-2, IL-4, IL-10 or interferon-gamma [84]. There is also no effect on the numbers of or the functional activities of neutrophils, monocytes or lymphocytes with moderate fish oil supplementation in healthy adults [85, 86]. Other studies have shown a reduction in cytokines as mentioned above [67, 70–72]. In view of these conflicting results further research is required to examine the effects on elderly patients.

Haemostasis

Patients with CHF are at increased risk of thromboembolism. Ingestion of n-3 fatty acids leads to suppression of TX_A2 synthesis by platelets and by blood mononuclear cells [87, 88]. Decreased platelet aggregation has been demonstrated with EPA supplementation in some [89– 91] but not all studies [92–94].

EPA can reduce the expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (E-selectin or ELAM-1) and intercellular adhesion molecule-1 (ICAM-1) [95]. These adhesion molecules are elevated in CHF and plasma levels are related to the severity of the condition [96, 97]. EPA and DHA suppress adherence of monocytes to activated endothelial cells also by affecting endothelial platelet aggregating factor (PAF) generation [98].

Endothelin 1

Endothelin 1 (ET-1) is a powerful vasoconstrictor [99] and higher levels of ET-1 predict a poor prognosis in CHF patients. EPA suppresses endothelin-1 (ET-1) production in human coronary artery smooth muscle cells [100].

Cachexia

Patients with severe CHF often lose weight. This is a consequence of the inflammatory processes, reduced intake and increased catabolism. Weight loss or frank cachexia is commonly seen in heart failure [101], the prevalence increasing with worsening symptoms [102, 103]. Cachexia worsens the already poor prognosis by a factor of 2.6 [102]. More subtle loss of muscle bulk occurs early in the disease [104].

There may be multiple aetiologies to the weight loss [105]. There is a general predominance of catabolic processes over anabolic in heart failure [106]. Catabolic steroids are elevated in untreated patients [107] and in treated patients there is an increase in catabolic relative to anabolic steroids [60, 108]. EPA is effective in attenuating the increased protein catabolism in cancer cachexia [109–111]. EPA also inhibits lipolysis [112].

Arrhythmias

Patients with chronic heart failure have a high incidence of sudden death [113]. One of the major effects seen in the GISSI-prevenzione post-infarction study was a reduction in sudden death by 45% [9]. There is an inverse association between blood levels of fish oils and sudden death [114]. Fish oils have been shown to have an anti-arrhythmic effect in vitro and in vivo [115–117], even when administered acutely [118–121]. They can prevent ischaemia-induced ventricular fibrillation [121]. The anti-arrhythmic effect is related to their ability to reduce the electrical excitability and automaticity of cardiac myocytes [118, 131]. They increase the electrical stimulus required to elicit an action potential by approximately 50% and prolong the relative refractory time by approximately 150% [122].

Fish oils can prevent or terminate the tachyarrhythmias induced by isoproterenol, or its intracellular messenger, cAMP [119]. Despite this, cardiomyocytes exposed to DHA have a greater chronotropic response to beta-agonists than those without this fish oil [123], possibly due to increased cAMP efficiency.

Secondary prevention trials of myocardial infarction survivors have suggested that high intakes of fish [10] and ALA [124] reduce the incidence of fatal cardiac arrhythmias. In survivors of acute myocardial infarction with left ventricular dysfunction, there was a correlation between platelet DHA, the patients' intake of fish and heart rate variability [125]. Human studies have demonstrated a reduction in ventricular extrasystoles [126], and increased heart rate variability with fish oil supplementation [127, 128]. Increased dietary intake of marine oils has been linked with a lower incidence of primary cardiac arrest [129]. By reducing sodium influx [130], and shortening the action potential [131], fish oils can shift the threshold for excitation to more positive potentials, and prolong the relative refractory period.

N-3 polyunsaturated marine oils prevent ischaemia-induced malignant cardiac arrhythmias in animal studies [115, 117, 132–138] The presence of fish oils accelerates the electrical depression during hypoxia but allow a faster recovery upon reoxygenation. By increasing the ratio of EPA to AA within cellular membranes there is an increase in the Ca²⁺-Mg²⁺-ATPase activity within myocardial membranes [139]. These cellular alterations reduce the severity of ventricular arrhythmias following the ischaemia by altering cardiac sarcoplasmic reticulum Ca-ATPase function, and thereby inhibiting the rapid accumulation of intracellular Ca²⁺ [140].

Despite the observed effects of fish oils on arrhythmic mortality in post-infarct patients, there are conflicting data in patients with automatic implantable cardioverter defibrillators (AICD) [141]. In a population of 200 patients over 2 years there was a non-significant trend to an increased risk of ventricular arrhythmia in patients randomized to n-3 fatty acids. Subgroup analysis suggested that patients who had received an AICD for sustained VT had more arrhythmias on fish oil, whilst patients enrolled with VF tended to have fewer. There were only two sudden deaths, both on fish oil but there was a strong trend for reduced overall mortality (P = 0.09) with fish oil. This trial suggests that if n-3 fatty acids do reduce mortality, they may do so by a mechanism other than reduction in ventricular arrhythmias. As the substrate for the induction of VT and VF may be different, a specific effect on VF suppression cannot be excluded. This is a small study though, with a small number of events and it is possible that the effects seen are due to chance.

Heart failure data

There are no published data examining the effects of fish oil supplementation in patients with CHF. One study examining cachexic heart failure in dogs demonstrated that fish oil supplementation decreased Il-1 concentrations and improved cachexia [142].

Patients with chronic heart failure die of ischaemic events [143], arrhythmias and deterioration of their heart failure. They are at greater risk of death if they are cachexic and have high circulating markers of inflammation. Fish oils lower blood pressure, reduce ischaemia, reduce platelet aggregation and prevent arrhythmias. They reduce inflammatory mediator production and lead to weight gain. Fish oil supplements have previously been limited by poor tolerability, but newer preparations are well tolerated allowing for high-dose supplementation and long-term use [144].

Summary

Fish oils might be of benefit in patients with both ischaemic and non-ischaemic CHF through several mechanisms. They have anti-ischaemic, anti-arrhythmic and antithrombotic activity. In patients with cachexia, whose outlook is particularly poor, they might have important anticachectic and anticytokine effects. The clinical implications of the changes in cellular immune responses that fish oils might cause remain unclear, but patients with CHF are already at increased risk of acute infections. Any trial involving elderly patients would have to proceed cautiously with interim analyses looking for an increased incidence of infection in those receiving fish oil supplementation. The present review has focused on systolic heart failure. It is possible that patients with diastolic heart failure might benefit from these agents through similar mechanisms.

The time has come for a randomized, controlled trial in CHF patients who have potentially much to gain from these agents and the results of the GISSI-CHF trial [141] are eagerly awaited.

Footnotes

Acknowledgements

The authors are grateful to Ms Julie Hannah of the Dietetic Department, Hull Royal Infirmary for advice and suggestions during the preparation of this manuscript.

References

Cowie

Mosterd

Wood

DA.

The epidemiology of heart failure.

Eur Heart J 1997; 18:208–225.

Braunwald

Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities.

N Engl J Med. 1997; 337: 1360–1369.

Brown

Cleland

JGF.

Influence of concomitant disease on patterns of hospitalisations in patients with heart failure from Scottish hospitals in 1995.

Eur Heart J 1998; 19:1063–1069.

Cleland

JGF

Swedberg

Poole-Wilson

PA.

Successes and failures of current treatment of heart failure.

Lancet 1998; 352(Suppl 1):19–28.

5 Cleland

Thygesen

Uretsky

Armstrong

Horowitz

Massie

. ATLAS investigators. Cardiovascular critical event pathways for the progression of heart failure; a report from the ATLAS study. Eur Heart J 2001; 22:1601–1612.

McMurray

McDonagh

Morrison

Dargie

HJ.

Trends in hospitalisation for heart failure in Scotland 1980–1990.

Eur Heart J 1993; 14:1158–1162.

7 Stewart

Greenfield

Hays

. Functional status and well-being of patients with chronic conditions. JAMA 1989; 262:907–913.

Sinclair

HM.

Deficiency of essential fatty acids and atherosclerosis.

Lancet 1956; i:381–383.

9 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354:447–455.

10.

10 Burr

Fehily

Gilbert

Rogers

Holliday

Sweetnam

. Effects of changes in fat, fish, and fibre intakes on death and myocardial re-infarction: Diet and Reinfarction Trial (DART). Lancet 1989; ii:757–761.

11.

11 Marchioli

Barzi

Bomba

. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time course analysis of the Gruppo Italiano per lo Stuio deela Sopravivenza nell'Infarcto Miocardico (GISSI)-Prevenzione. Circulation 2002; 105:1897–1903.

12.

Wigmore

Ross

Falconer

Plester

Tisdale

Carter

Fearon

KC.

The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer.

Nutrition 1996; 12(Suppl 1): S27–S30.

13.

Barber

MD.

Cancer cachexia and its treatment with fish-oil-enriched nutritional supplementation.

Nutrition 2001; 17:751–755.

14.

Simopoulos

AP.

v-3 Fatty acids in health and disease and in growth and development.

Am J Clin Nutr 1991; 54:438–463.

15.

Bang

Dyergerg

Sinclair

HM.

The composition of the Eskimo food in north western Greenland.

Am J Clin Nutr 1980; 33:2657–2661.

16.

Hrelia

Lopez Jimenez

Bordoni

Nvarro

Horrobin

Rossi

Biagi

PL.

Essential fatty acid metabolism in cultured rat cardiomyocytes in response to either N-6 or N-3 fatty acid supplementation.

Biochem Biophys Res Commun 1995; 216:11–19.

17.

Lands

WEM

Morris

Libelt

Quantitative effects of dietary polyunsaturated fats on the composition of fatty acids in rat tissues.

Lipids 1990; 25:505–516.

18.

18 Lands

WEM

Libelt

Morris

. Maintenance of lower pro-portions of (n-6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n-3) fatty acids. Biochim Biophys Acta 1992; 1180: 147–162.

19.

Cleland

Gibson

Neumann

Hamazaki

Akimoto

James

MJ.

Dietary (n-29) eicosatrienoic acid from a cultured fungus inhibits leukotriene B 4 synthesis in rats and the effect is modified by dietary linoleic acid.

J Nutr 1996; 126:1534–1540.

20.

Cleland

James

Neumann

D'Angelo

Gibson

RA.

Linoleate inhibits EPA incorporation from dietary fish-oil supplements in human subjects.

Am J Clin Nutr 1992; 55:395–399.

21.

Morris

Sacks

Rosner

Does fish oil lower blood pressure? A meta-analysis of controlled trials.

Circulation 1993; 88:523–533.

22.

Mori

Bao

Burke

Puddey

Beilin

LJ.

Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans.

Hypertension 1999; 34:253–260.

23.

Geleijnse

Giltay

Grobbee

Donders

Kok

FJ.

Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials.

J Hypertens 2002; 20:1493–1499.

24.

Chin

JP.

Marine oils and cardiovascular reactivity.

Prostaglandins Leukot Essent Fatty Acids 1994; 50:211–222.

25.

Engler

MM.

Docosahexaenoic acid-induced vasorelaxation in hypertensive rats: mechanisms of action.

Biol Res Nurs 2000; 2: 85–95.

26.

Bayorh

McGee

Feuerstein

Acute and chronic effects of eicosapentaenoic acid (EPA) on the cardiovascular system.

Res Commun Chem Pathol Pharmacol 1989; 66:355–374.

27.

Engler

Pierson

Molteni

Effects of docosahexaenoic acid on vascular pathology and reactivity in hypertension.

Exp Biol Med (Maywood) 2003; 228:299–307.

28.

Cobiac

Nestel

Wing

Howe

PR.

A low-sodium diet supplemented with fish oil lowers blood pressure in the elderly.

J Hypertens 1992; 10:87–92.

29.

Kenny

The paradoxical effects of dietary fish oil on blood pressure.

Med Hypotheses 1992; 37:97–99.

30.

Triboulot

Hichami

Denys

Khan

NA.

Dietary (n-3) polyunsaturated fatty acids exert antihypertensive effects by modulating calcium signaling in T cells of rats.

J Nutr 2001; 131:2364–2369.

31.

Shimokawa

Lam

Chesebro

Bowie

Vanhoutte

PM.

Effects of dietary supplementation with cod-liver oil on endotheliumdependent responses in porcine coronary arteries.

Circulation 1987; 76:898–905.

32.

Friedberg

Janssen

Heine

Grobbee

DE.

Fish oil and glycemic control in diabetes. A meta-analysis.

Diabetes Care 1998; 21:494–500.

33.

Montori

Farmer

Wollan

Dinneen

SF.

Fish oil supplementation in type 2 diabetes: a quantitative systematic review.

Diabetes Care 2000; 23:1407–1415.

34.

Nordoy

Hansen

Brox

The effects of atorvastatin and omega-3 fatty acids on LDL subfractions and postprandial hyperlipidemia in patients with combined hyperlipidemia.

Nutr Metab Cardiovasc Dis 2001; 11:7–16.

35.

Woodman

Mori

Burke

Puddey

Watts

Beilin

LJ.

Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension.

Am J Clin Nutr 2002; 76:1007–1015.

36.

Friday

Childs

Tsunehara

Fujimoto

Bierman

Ensinck

JW.

Elevated plasma glucose and lowered triglyceride levels from omega-3 fatty acid supplementation in type II diabetes.

Diabetes Care 1989; 12:276–281.

37.

Glauber

Wallace

Griver

Brechtel

Adverse metabolic effect of omega-3 fatty acids in non-insulin-dependent diabetes mellitus.

Ann Intern Med 1988; 108:663–668.

38.

Eunyoung

Rexrode

Albert

Manson

JE.

Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.

Circulation 2003; 107:1852–1857.

39.

Ascherio

Rimm

Stampfer

Giovannucci

Willett

WC.

Dietary intake of marine n-3 fatty acids, fish intake and the risk of coronary disease among men.

N Engl J Med 1995; 332:977–982.

40.

40 Albert

Hennekens

O'Donnell

. Fish consumption and risk of sudden cardiac death. JAMA 1998; 279:23–28.

41.

Kromhout

Bosschieter

de Lezenne

CC.

The inverse relationship between fish consumption and 20-year mortality from coronary heart disease.

N Engl J Med 1985; 312:1205–1209.

42.

42 Daviglus

Stamler

Orencia

. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med 1997; 336: 1046–1053.

43.

Dolecek

TA.

Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial.

Proc Soc Exp Biol Med 1992; 200:177–182.

44.

44 Rodriguez

Sharp

Abbott

. Fish intake may limit the increase in risk of coronary heart disease morbidity and mortality among heavy smokers: The Honolulu Heart Program. Circulation 1996; 94:952–956.

45.

Ness

Hughes

Elwood

Whitley

Smith

Burr

ML.

The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART).

Eur J Clin Nutr 2002; 56: 512–518.

46.

Pepe

McLennan

PL.

Cardiac membrane fatty acid composition modulates myocardial oxygen consumption and postischemic recovery of contractile function.

Circulation 2002; 105:2303–2308.

47.

Mehta

Lopez

Lawson

Wargovich

Williams

LL.

Dietary supplementation with omega-3 polyunsaturated fatty acids in patients with stable coronary heart disease. Effects on indices of platelet and neutrophil function and exercise performance.

Am J Med 1988; 84:45–52.

48.

Vandongen

Mori

Burke

Beilin

Morris

Ritchie

Effects on blood pressure of omega 3 fats in subjects at increased risk of cardiovascular disease.

Hypertension 1993; 22:371–379.

49.

Grimsgaard

Bønaa

Hansen

J-B

Myhre

ESP.

Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemodynamics in humans 1–3.

Am J Clin Nutr 1998; 68:52–59.

50.

McLennan

Barnden

Bridle

Abeywardena

Charnock

JS.

Dietary fat modulation of left ventricular ejection fraction in the marmoset due to enhanced filling.

Cardiovasc Res 1992; 26:871–877.

51.

51 Ventura

Milani

Lavie

. Cyclosporine-induced hypertension. Efficacy of omega-3 fatty acids in patients after cardiac transplantation. Circulation 1993; 88:II281–II285.

52.

Nishimura

Nanbu

Komori

Ohtsuka

Takahashi

Yoshimura

Eicosapentaenoic acid stimulates nitric oxide production and decreases cardiac noradrenaline in diabetic rats.

Clin Exp Pharmacol Physiol 2000; 27:618–624.

53.

Hayashi

Nasa

Tanonaka

Sasaki

Miyake

Hayashi

Takeo

The effects of long-term treatment with eicosapentaenoic acid and docosahexaenoic acid on hypoxia/rexoygenation injury of isolated cardiac cells in adult rats.

J Mol Cell Cardiol 1995; 27:2031–2041.

54.

Otsuji

Shibata

Hirota

Akagami

Wada

Highly purified eicosapentaenoic acid attenuates tissue damage in experimental myocardial infarction.

Jpn Circ J 1993; 57:335–343.

55.

Zhu

Sievers

Sun

Morse-Fisher

Parmley

Wolfe

CL.

Is the reduction of myocardial infarct size by dietary fish oil the result of altered platelet function?

Am Heart J 1994; 127:744–755.

56.

Dusing

Struck

Gobel

Weisser

Vetter

Effects of n-3 fatty acids on renal function and renal prostaglandin E metabolism.

Kidney Int 1990; 38:315–319.

57.

57 Holm

Andreassen

Aukrust

Andersen

Geiran

Kjekshus

. Omega-3 fatty acids improve blood pressure control and preserve renal function in hypertensive heart transplant recipients. Eur Heart J 2001; 22:428–436.

58.

58 Levine

Kalman

Mayer

. Elevated circulating levels of tumour necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323:236–241.

59.

59 Anker

Ponikowski

Clark

Leyva

Rauchhaus

Kemp

. Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure. Eur Heart J 1999; 20: 683–693.

60.

60 Anker

Clark

Kemp

. Tumour necrosis factor and steroid metabolism in chronic heart failure: possible relation to muscle wasting. J Am Coll Cardiol 1997; 30:997–1001.

61.

Zhao

Zeng

LH.

Elevated plasma levels of tumour necrosis factor in chronic heart failure with cachexia.

Int J Cardiol 1997; 58:257–261.

62.

62 Seta

Shan

Bozkurt

. Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail 1996; 3:243–249.

63.

Berkowitz

Brown

Lee

KM.

Endotoxin-induced alteration in the expression of leptin and beta-3 adrenergic receptor in adipose tissue.

Am J Physiol 1998; 274:992–997.

64.

Mantzoros

Moschos

Avramopoulos

Leptin concentrations in relation to body mass index and the tumour necrosis factor-alpha system in humans.

J Clin Endocrinol Metab 1997; 82:3408–3413.

65.

Arend

Dayer

J-M.

Inhibition of the production and effects of interleukin-1 and tumor necrosis factor a in rheumatoid arthritis.

Arthritis Rheum 1995; 38:151–160.

66.

Dinarello

CA.

Interleukin-1 and its biologically related cytokines.

Adv Immunol 1989; 44:153–205.

67.

Pakala

Sheng

Benedict

CR.

Vascular smooth muscle cells preloaded with eicosapentaenoic acid and docosahexaenoic acid fail to respond to serotonin stimulation.

Atherosclerosis 2000; 153: 47–57.

68.

Caughey

Mantzioris

Gibson

Cleland

James

MJ.

The effect on human tumor necrosis factor-α and interleukin 1β production of diets enriched in n-3 fatty acids from vegetable oil or fish oil.

Am J Clin Nutr 1996; 63:116–122.

69.

Bagga

Wang

Farias-Eisner

Glaspy

Reddy

ST.

Differential effects of prostaglandin derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion.

Proc Natl Acad Sci USA 2003; 100:1751–1756.

70.

70 Endres

Ghorbani

Kelley

. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989; 320:265–271.

71.

71 Meydani

Endres

Woods

. Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between younger and older women. J Nutr 1991; 121:547–555.

72.

72 Kremer

Lawrence

Jubiz

. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Arthritis Rheum 1990; 33:810–820.

73.

Chiu

Helton

Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity.

J Surg Res 1999; 82:216–221.

74.

Khalfoun

Thibault

Watier

Bardos

Lebranchu

Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6.

Adv Exp Med Biol 1997; 400B:589–597.

75.

Shimizu

Iwamoto

Itou

Iwata

Endo

Takasaki

Effect of ethyl icosapentaenoate (EPA) on the concentration of tumor necrosis factor (TNF) and interleukin-1 (IL-1) in the carotid artery of cuff-sheathed rabbit models.

J Atheroscler Thromb 2001; 8:45–49.

76.

Hawkes

James

Cleland

LG.

Biological activity of prostaglandin E 3 with regard to oedema formation in mice.

Agents Actions 1992; 35:85–87.

77.

Hawkes

James

Cleland

LG.

Separation and quantification of PGE 3 following derivatization with panacyl bromide by high pressure liquid chromatography with fluorometric detection.

Prostaglandins 1991; 42:355–368.

78.

James

Cleland

Gibson

Hawkes

JS.

Interaction between fish and vegetable oils in relation to rat leucocyte leukotriene production.

J Nutr 1991; 121:631–637.

79.

Goldman

Pickett

Goetzl

EJ.

Human neutrophil chemotactic and degranulating activities of leukotriene B 5 (LTB 5) derived from eicosapentaenoic acid.

Biochem Biophys Res Commun 1983; 117: 282–288.

80.

Miles

Allen

Calder

PC.

In vitro effects of eicosanoids derived from different 20-carbon Fatty acids on production of monocyte-derived cytokines in human whole blood cultures.

Cytokine 2002; 20:215–223.

81.

Anderson

Fritsche

KL.

(n-3) Fatty acids and infectious disease resistance.

J Nutr 2002; 132:3566–3576.

82.

Switzer

McMurray

Morris

Chapkin

RS.

(n-3) Polyunsaturated fatty acids promote activation-induced cell death in murine T lymphocytes.

J Nutr 2003; 133:496–503.

83.

Bechoua

Dubois

Vericel

Chapuy

Lagarde

Prigent

AF.

Influence of very low dietary intake of marine oil on some functional aspects of immune cells in healthy elderly people.

Br J Nutr 2003; 89:523–531.

84.

Wallace

Miles

Calder

PC.

Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects.

Br J Nutr 2003; 89:679–689.

85.

85 Kew

Banerjee

Minihane

Finnegan

Muggli

Albers

. Lack of effect of foods enriched with plant- or marine-derived n-3 fatty acids on human immune function. Am J Clin Nutr 2003; 77:1287–1295.

86.

Thies

Miles

Nebe-von-Caron

Powell

Hurst

Newsholme

Calder

PC.

Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults.

Lipids 2001; 36:1183–1193.

87.

Caughey

Pouliot

Cleland

James

MJ.

Regulation of tumor necrosis factor alpha and interleukin-1 beta synthesis by thromboxane A 2 in non-adherent human monocytes.

J Immunol 1997; 158:351–358.

88.

Caughey

Mantzioris

Gibson

Cleland

James

MJ.

The effect on human tumor necrosis factor-α and interleukin 1β production of diets enriched in n-3 fatty acids from vegetable oil or fish oil.

Am J Clin Nutr 1996; 63:116–122.

89.

von Schacky

Weber

PC.

Metabolism and effects on platelet function of the purified eicosapentaenoic and docosahexaenoic acids in humans.

J Clin Invest 1985; 76:2446–2450.

90.

Nieuwenhuys

Feijge

Offermans

Kester

Hornstra

Heemskerk

JW.

Modulation of rat platelet activation by vessel wall-derived prostaglandin and platelet-derived thromboxane: effects of dietary fish oil on thromboxane-prostaglandin balance.

Atherosclerosis 2001; 154: 355–366.

91.

91 Mezzano

Kosiel

Martinez

Cuevas

Panes

Aranda

. Cardiovascular risk factors in vegetarians. Normalization of hyperhomocysteinemia with vitamin B(12) and reduction of platelet aggregation with n-3 fatty acids. Thromb Res 2000; 100:153–160.

92.

Woodman

Mori

Burke

Puddey

Barden

Watts

Beilin

LJ.

Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients.

Atherosclerosis 2003; 166:85–93.

93.

Svaneborg

Kristensen

Hansen

Bullow

Husted

Schmidt

EB.

The acute and short-time effect of supplementation with the combination of n-3 fatty acids and acetylsalicylic acid on platelet function and plasma lipids.

Thromb Res 2002; 105:311–316.

94.

Knapp

HR.

Dietary fatty acids in human thrombosis and hemostasis.

Am J Clin Nutr 1997; 65(5 Suppl):1687S–1698S.

95.

95 Kim

Eastman

Baker

Mastrangelo

Sethi

Ross

. Fish oil, atherogenesis, and thrombogenesis. Ann NY Acad Sci 1995; 748: 474–480.

96.

96 Andreassen

Nordoy

Simonsen

Ueland

Muller

Froland

. Levels of circulating adhesion molecules in congestive heart failure and after heart transplantation. Am J Cardiol 1998; 81:604–608.

97.

Tousoulis

Homaei

Ahmed

Asimakopoulos

Zouridakis

Toutouzas

Davies

GJ.

Increased plasma adhesion molecule levels in patients with heart failure who have ischemic heart disease and dilated cardiomyopathy.

Am Heart J 2001; 141:277–280.

98.

98 Mayer

Merfels

Muhly-Reinholz

Gokorsch

Rosseau

Lohmeyer

. Omega-3 fatty acids suppress monocyte adhesion to human endothelial cells: role of endothelial PAF generation. Am J Physiol Heart Circ Physiol 2002; 283:H811–818.

99.

Cohn

JN.

Is there a role for endothelin in the natural history of heart failure?

Circulation 1996; 94:604–606.

100.

100 Kohno

Ohmori

Wada

Kondo

Noma

Fujita

. Inhibition by eicosapentaenoic acid of oxidized-LDL- and lysophosphatidylcholineinduced human coronary artery smooth muscle cell production of endothelin. J Vasc Res 2001; 38:379–388.

101.

101

Schwengel

Gottlieb

Fisher

ML.

Protein-energy malnutrition in patients with ischaemic and non-ischaemic dilated cardiomyopathy and congestive heart failure.

Am J Cardiol 1994; 73:908–910.

102.

102 Anker

Ponikowski

Varney

. Wasting as an independent risk factor for mortality in chronic heart failure. Lancet 1997; 349:1050–1053.

103.

103

Carr

Stevenson

Walden

Heber

Prevalence and haemodynamic correlates of malnutrition in severe congestive heart failure secondary to ischaemic or idiopathic dilated cardiomyopathy.

Am J Cardiol 1989; 63:709–713.

104.

104 Mancini

Walter

Reichnek

. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992; 85:1364–1373.

105.

105

Pittman

Cohen

The pathogenesis of cardiac cachexia.

N Engl J Med 1964; 271:453–460.

106.

106

Berry

Clark

AL.

Catabolism in chronic heart failure.

Eur Heart J 2000; 21:521–532.

107.

107 Anand

Ferrari

Kalra

. Edema of cardiac origin. Studies of body water and sodium, renal function, haemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation 1989; 80:299–305.

108.

108 Anker

Chua

Ponikowski

. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 1997; 96:526–534.

109.

109

Barber

Ross

Voss

Tisdale

Fearon

KC.

The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer.

Br J Cancer 1999; 81:80–86.

110.

110

Whitehouse

Tisdale

MJ.

Downregulation of ubiquitin-dependent proteolysis by eicosapentaenoic acid in acute starvation.

Biochem Biophys Res Commun 2001; 285:598–602.

111.

111

Lorite

Cariuk

Tisdale

MJ.

Induction of muscle protein degradation by a tumour factor.

Br J Cancer 1997; 76:1035–1040.

112.

112

Price

Tisdale

MJ.

Mechanism of inhibition of a tumor lipid-mobilizing factor by eicosapentaenoic acid.

Cancer Res 1998; 58:4827–4831.

113.

113

Cleland

Massie

Packer

Sudden death in heart failure: vascular or electrical?

Eur J Heart Fail 1999; 1:41–45.

114.

114 Albert

Campos

Stampfer

. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002; 346: 1113–1118.

115.

115

McLennan

Abeywardena

Charnock

JS.

Influence of dietary lipids on arrhythmias and infarction after coronary artery ligation in rats.

Can J Physiol Pharmacol 1985; 63:1411–1417.

116.

116

Charnock

JS.

Dietary fats and cardiac arrhythmia in primates.

Nutrition 1994; 10:161–169.

117.

117

Hock

Beck

Bodine

Reibel

DK.

Influence of dietary n-3 fatty acids on myocardial ischemia and reperfusion.

Am J Physiol 1990; 259:H1518–H1526.

118.

118

Kang

Leaf

Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes.

Proc Natl Acad Sci USA 1994; 91:9886–9890.

119.

119

Kang

Leaf

Prevention and termination of the beta-adrenergic agonist-induced arrhythmias by free polyunsaturated fatty acids in neonatal rat cardiac myocytes.

Biochem Biophys Res Commun 1995; 208: 629–636.

120.

120

Kang

Leaf

Protective effects of free polyunsaturated fatty acids on arrhythmias induced by lysophosphatidylcholine or palmitoylcarnitine in neonatal rat cardiac myocytes.

Eur J Pharmacol 1996; 297:97–106.

121.

121

Billman

Hallaq

Leaf

Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids.

Proc Natl Acad Sci USA 1994; 91:4427–4430.

122.

122

Kang

Leaf

Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids.

Am J Clin Nutr 2000; 71:202S–207S.

123.

123

Grynberg

Fournier

Sergiel

Athias

Effect of docosahexaenoic acid and eicosapentaenoic acid in the phospholipids of rat heart muscle cells on adrenoceptor responsiveness and mechanism.

J Mol Cell Cardiol 1995; 27:2507–2520.

124.

124 de Lorgeril

Renaud

Mamelle

. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343:1454–1459.

125.

125 Christensen

Korup

Aaroe

Toft

Moller

Rasmussen

. Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol 1997; 79:1670–1673.

126.

126

Sellmayer

Witzgall

Lorenz

Weber

PC.

Effects of dietary fish oil on ventricular premature complexes.

Am J Cardiol 1995; 76: 974–977.

127.

127 Christensen

Gustenhoff

Korup

. Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial. BMJ 1996; 312:677–678.

128.

128

Villa

Calabresi

Chiesa

Rise

Galli

Sirtori

Omega-3 fatty acid ethyl esters increase heart rate variability in patients with coronary disease.

Pharmacol Res 2002; 45:475.

129.

129 Siscovick

Raghunathan

King

. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995; 274:1363–1367.

130.

130

Xiao

Kang

Morgan

Leaf

Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes.

Proc Natl Acad Sci USA 1995; 92:1100–1104.

131.

131

Kang

Xiao

Leaf

Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes.

Proc Natl Acad Sci USA 1995; 92:3997–4001.

132.

132

McLennan

Bridle

Abeywardena

Charnock

JS.

Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey.

Am Heart J 1992; 123:1555–1561.

133.

133

Billman

Hallaq

Leaf

Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids.

Proc Natl Acad Sci USA 1994; 91:4427–4430.

134.

134

McLennan

PL.

Relative effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on cardiac arrhythmias in rats.

Am J Clin Nutr 1993; 57:207–212.

135.

135

Billman

Kang

Leaf

Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs.

Circulation 1999; 99:2452–2457.

136.

136 Burr

Gilbert

Holliday

Elwood

Fehily

Rogers

. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989; 334: 757–761.

137.

137 de Logeril

Renaud

Mamelle

Salen

Martin

J-L

Monjaud

. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343:1454–1459.

138.

138 Siscovick

Raghunathan

King

Weinmann

Wicklund

Albright

. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. J Am Med Assoc 1995; 274:1363–1367.

139.

139

Kinoshita

Itoh

Nishida-Nakai

Hirota

Otsuji

Shibata

Antiarrhythmic effects of eicosapentaenoic acid during myocardial infarction–enhanced cardiac microsomal (Ca2+-Mg2+)-ATPase activity.

Jpn Circ J 1994; 58:903–912.

140.

140

Taffet

Pham

Bick

Entman

Pownall

Bick

RJ.

The calcium uptake of the rat heart sarcoplasmic reticulum is altered by dietary lipid.

J Membr Biol 1993; 131:35–42.

141.

141 Cleland

JGF

Freemantle

Kaye

Nasir

Velavan

Lalukota

. Clinical trials update from the American Heart Association meeting: Omega-3 fatty acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF V, ORBIT and PAD and DEFINITE. Eur J Heart Fail 2004; 6:109–115.

142.

142 Freeman

Rush

Kehayias

Ross

Jr Meydani

Brown

. Nutritional alterations and the effect of fish oil supplementation in dogs with heart failure. J Vet Intern Med 1998; 12:440–448.

143.

143

Yusuf

Pepine

Garces

Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions.

Lancet 1992; 340:1173–1178.

144.

144 Harris

Ginsberg

Arunakul

Shachter

Windsor

Adams

. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk 1997; 4:385–391.