Nytta och risk med konsumtion av fet fisk

Uppsala, okt.2002

Jørn DyerbergJørn Dyerberg

Hjärta/kärlaspekter, Hjärta/kärlaspekter,

omega-3-fettsyroromega-3-fettsyror

Age standardised death rates in per cent of all deaths from IHD in males aged 45-64 yearsFigures in Greenland based on the years 1974-76.

IHD deathsIHD deaths

U.S.U.S. 40,440,4

DenmarkDenmark 34,734,7

GreenlandGreenland 5,35,3

Lancet 1971; 1:1143-6

Fatty acid composition of plasma phospholipids in Greenland Eskimos GE and Danish controls D. Values are means as per cent of total (Am J Clin Nutr 1975;28:958-66)

GEGE DD

8:0 – 15:08:0 – 15:0 4.24.2 0.30.3

16:016:0 32.232.2 30.030.0

16:116:1 4.34.3 0.80.8

16:2 – 17:116:2 – 17:1 -- 0.70.7

18:018:0 17.017.0 14.614.6

18:118:1 14.914.9 12.412.4

18:218:2 5.45.4 22.322.3

18:318:3 0.10.1 0.20.2

18:4 – 20:318:4 – 20:3 3.33.3 0.70.7

20:420:4 3.83.8 7.47.4

20:520:5 7.47.4 1.81.8

22:0 – 22:522:0 – 22:5 2.22.2 2.22.2

22:622:6 3.63.6 2.22.2

24:0 – 24:124:0 – 24:1 2.52.5 4.24.2

SaturatedSaturated 54.554.5 47.347.3

MonoenesMonoenes 24.424.4 15.315.3

PolyenesPolyenes 21.121.1 34.234.2

20:5/20:420:5/20:4 1.951.95 0.240.24

Lancet 1978; 2:1179

Distribution of fatty acid classes in Danish and Eskimo food and blood platelets

FoodFood

Omega-6 class__________________________________Omega-6 class__________________________________

Omega-3 class__________________________________Omega-3 class__________________________________

PlateletsPlatelets

Arachidonic acid (Omega-6)_______________________Arachidonic acid (Omega-6)_______________________

Eicosapentaenoic acid (Omega-3)___________________Eicosapentaenoic acid (Omega-3)___________________

Bleeding Time_____________________________________Bleeding Time_____________________________________

EskimosEskimos5,4 g/day5,4 g/day

13,7 g/day13,7 g/day

8,5 %8,5 %8,0 %8,0 %

8,1 min8,1 min

DanesDanes10,0 g/day10,0 g/day2,8 g/day2,8 g/day

22,1 %22,1 %0,5 %0,5 %

4,7 min4,7 min

Lancet 1979;2:433-5

The effect of n-3 PUFA supplementation on bleeding time (BT) in normals and different patient groups

n-3 PUFAn-3 PUFA DurationDuration Median BT (min)Median BT (min)

Patient groupPatient group nn g/day g/day (weeks)(weeks) beforebefore afterafter p valuep value

Angina pectorisAngina pectoris11 3636 4.54.5 1212 55 5½5½ N.S.N.S.

IDDMIDDM22 1010 44 66 55 5½5½ 0.05<p<0.100.05<p<0.10

HyperlipemiaHyperlipemia33 1717 66 66 55 66 <0.05<0.05

HypertensionHypertension44 1010 44 66 66 6½6½ N.S.N.S.

NormalsNormals55 1010 44 66 55 6½6½ <0.05<0.05

NormalNormal66 2020 44 44 55 5½5½ <0.05<0.05

1.1. Kristiansen et al. Atherosclerosis 1987; 13-9Kristiansen et al. Atherosclerosis 1987; 13-92.2. Schmidt et al. J Intern Med 1989; (suppl 1) : 201-6Schmidt et al. J Intern Med 1989; (suppl 1) : 201-63.3. Schmidt et al. Thromb Haemostas 1989; 62: 797-801Schmidt et al. Thromb Haemostas 1989; 62: 797-8014.4. Schmidt et al. Clin Chim Acta 1990; 189; 25-32Schmidt et al. Clin Chim Acta 1990; 189; 25-325.5. Schmidt et al. Thromb Haemostas 1990; 63: 1-5Schmidt et al. Thromb Haemostas 1990; 63: 1-56.6. Mortensen et al. Thromb Haemostas 1983; 30: 543-6. Mortensen et al. Thromb Haemostas 1983; 30: 543-6.

Gissi-Prevenzione trial

2830 given n-3 PUFAplus vitamin E

11324 patients randomised

3 lost to follow-up768 discontinued

n-3 PUFA

4 lost to follow-up687 discontinued

vitamin E11 receivedn-3 PUFA

4 lost to follow-up848 discontinued

n-3 PUFA808 discontinued

vitamin E

2 lost to follow-up15 receivedn-3 PUFA2 receivedvitamin E

2836 analysedfor outcomes

2830 analysedfor outcomes

2830 analysedfor outcomes

2828 analysedfor outcomes

2828controls

2830 given vitamin E2830 given n-3 PUFA

Lancet 1999; 354: 447-55

Figure 1: Trial profile

GISSI – Preventione TrialResults (RR Four-way analysis)

n-PUFAn-PUFA

All fatal eventsAll fatal events 0.80 (p = 0.008)0.80 (p = 0.008)

CV deathsCV deaths 0.70 (p = 0.0242)0.70 (p = 0.0242)

Sudden deathSudden death 0.55 (0 = 0.010)0.55 (0 = 0.010)

Death, non-fatal MI, and non-fatal Death, non-fatal MI, and non-fatal strokestroke

0.85 (p = 0.023)0.85 (p = 0.023)

Cardiovascular death, non-fatal MI, Cardiovascular death, non-fatal MI, and nonfatal strokeand nonfatal stroke

0.80 (p = 0.008)0.80 (p = 0.008)

Lancet 1999;Lancet 1999; 254254: 4475-54475-5

Heart Rate Variability

Standards of Measurement, Physiological Interpretation, and Clinical Use

Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology

“Because 24-hour HRV indices appear to be stable and free of placebo effect, they may be ideal variables to assess intervention therapies”

“A powerful predictor of SCD”

Circulation 1996;93:1043

Special Report

Lav HFV

Høj HFV

Omega-3 fedtsyrer og pludselig hjertedød

DHA i trombocytterlav mellem høj

(Am J Cardiol 1997;79:1670)

Patienter med AMI og EF < 0.40

80

120

160SDNN (ms)

1. kvartil 2.-3. kvartil 4. kvartil

HRV and DHA in healthy men

r = 0.50, p<0.01r = 0.50, p<0.01---------Lowess ---------Lowess regressionregression______linear regression______linear regression

r = 0.68, p<0.001 in the r = 0.68, p<0.001 in the interval 1.3<DHA<2.1interval 1.3<DHA<2.1

Content of DHA in granulocytesContent of DHA in granulocytes

Am J Clin Nutr 1999;70:333-7

H R V in H e a lth y M en w ith a b a se lin e S D N N < 1 5 0 m s

1 2 0

1 2 5

1 3 0

1 3 5

1 4 0

1 4 5

1 5 0

2 .0 g o f O m e g a -3 fa t ty a c id s 6 .6 g o f O m e g a -3 fa tty a c id s

= b e fo re

= a fte r

*S D N N (m s)

Am J Clin Nutr 1999;70:331-7

Marine n-3 Fatty Acids, Wine Intake, and Heart RateVariability in Patients Referred for Coronary Angiography

Circulation 2001;103:651

295 patients referred for elective coronary angiography

Food questionnaire and drinking habits

Adipose tissue biopsy (n-3 fatty acids)

Granulocytes and platelets (n-3 fatty acids)

24-hour HRV

Table 2. Fish Consumption (Fish Score) Related to n-3 PUFA Levels

Fish ScoreFish Score

2-42-4

(n=29)(n=29)

5-65-6

(n=49)(n=49)

7-87-8

(n=91)(n=91)

9-109-10

(n-113)(n-113)

11-1211-12

(n=19)(n=19)

GranulocytesGranulocytes

EPA, %EPA, % 0.63 (0.3)0.63 (0.3) 0.68 (0.3)0.68 (0.3) 0.77 (0.4)0.77 (0.4) 1.02 (0.5)1.02 (0.5) 1.12 (0.5)*1.12 (0.5)*

DHA, %DHA, % 1.34 (0.4)1.34 (0.4) 1.52 (0.4)1.52 (0.4) 1.59 (0.4)1.59 (0.4) 1.88 (0.5)1.88 (0.5) 1.81 (0.5)*1.81 (0.5)*

Total n-3Total n-3

PUFA %PUFA %

3.30 (0.8)3.30 (0.8) 3.56 (1.0)3.56 (1.0) 3.82 (1.0)3.82 (1.0) 4.56 (1.3)4.56 (1.3) 4.41 (1.2)*4.41 (1.2)*

Adipose tissueAdipose tissue

EPA, %EPA, % 0.09 (0.04)0.09 (0.04) 0.11 (0.04)0.11 (0.04) 0.12 (0.05)0.12 (0.05) 0.14 (0.05)0.14 (0.05) 0.16 (0.05)*0.16 (0.05)*

DHA, %DHA, % 0.23 (0.09)0.23 (0.09) 0.30 (0.12)0.30 (0.12) 0.34 (0.14)0.34 (0.14) 0.40 (0.16)0.40 (0.16) 0.46 (0.18)*0.46 (0.18)*

Total n-3Total n-3

PUFA %PUFA %

0.60 (0.19)0.60 (0.19) 0.71 (0.23)0.71 (0.23) 0.79 (0.25)0.79 (0.25) 0.88 (0.29)0.88 (0.29) 0.96 (0.29)*0.96 (0.29)*

The mean levels (SD) of the n-3 PUFA eicosapentaenoic acid (EPA) and DHA in granulocyte The mean levels (SD) of the n-3 PUFA eicosapentaenoic acid (EPA) and DHA in granulocyte membranes and in adipose tissue are givenmembranes and in adipose tissue are given

*p<0.001 (Kruskal-Wallis test)*p<0.001 (Kruskal-Wallis test)

Cirkulation 2001; 103: 651-7Cirkulation 2001; 103: 651-7

Table 3. Univariate Nonparametric Correlation Coefficients Between Levels of n-3 PUFA in Adipose Tissue and in Granulocyte Membranes and HRV Indices in the 291 Patients

Adipose TissueAdipose Tissue Granulocyte MembranesGranulocyte Membranes

EPAEPA DHADHA Total n-3 PUFATotal n-3 PUFA EPAEPA DHADHA Total n-3 PUFATotal n-3 PUFA

RRRR 0.0870.087 0.121*0.121* 0.124*0.124* 0.130*0.130* 0.1660.166†† 1.150*1.150*

SDNNSDNN -0.002-0.002 0.0440.044 0.0280.028 0.0880.088 0.150*0.150* 0.132*0.132*

SDNN SDNN indexindex

0.0480.048 0.122*0.122* 0.1010.101 0.167 0.167 †† 0.214 0.214 †† 0.191 0.191 ††

SDANN SDANN indexindex

-0.012-0.012 0.0100.010 0.0000.000 0.0630.063 0.124*0.124* 0.1130.113

RMSSDRMSSD 0.0330.033 0.138*0.138* 0.1150.115 0.0830.083 0.152*0.152* 0.1010.101

PNN50PNN50 0.0350.035 0.1340.134 0.1140.114 0.0710.071 0.137*0.137* 0.0840.084

**pp<0.05; <0.05; ††pp<0.01<0.01

Cirkulation 2001; 103: 651-7Cirkulation 2001; 103: 651-7

**: p<0.01, Kruskall-Wallis test

**: p<0.01, Kruskall-Wallis test

**: p<0.01, Kruskall-Wallis test

Table 5. Linear Multiple Regression Analysis (Backward) With HRV Indices as Dependent Factors

Modifiable FactorsModifiable FactorsNonmodifiableNonmodifiable

FactorsFactorsMedicationMedication n-3 PUFA Relatedn-3 PUFA Related LifestyleLifestyle

RRRR -Blocker-Blocker†† DHA(g), DHA(g), † n-3 PUFA(a)*† n-3 PUFA(a)* Tobacco Tobacco †† Age Age ††

SDNNSDNN -Blocker*-Blocker* DHA(g)*DHA(g)* Tobacco Tobacco †† MI*MI*

SDNNindexSDNNindexDHA(g), DHA(g), † n-3 PUFA(g),*† n-3 PUFA(g),*

EPA(g),* EPA(a)*EPA(g),* EPA(a)*Tobacco Tobacco ††

SCANNindexSCANNindex -Blocker -Blocker †† DHA(g)*DHA(g)* Tobacco Tobacco ††

RMSSDRMSSD -Blocker*-Blocker*EPA(a), EPA(a), † n-3 PUFA(a), † † n-3 PUFA(a), †

EPA(g)*EPA(g)*Age*Age*

PNN50PNN50 -Blocker*-Blocker*EPA(g),* DHA(g),* EPA(a), EPA(g),* DHA(g),* EPA(a), †, n-†, n-

3 PUFA(a) †3 PUFA(a) †

Backward linear multiple regression analysis was conducted with the following independent Backward linear multiple regression analysis was conducted with the following independent modifiable factors: (1) body mass index; medical therapy with (2) ACE inhibitors, (3) modifiable factors: (1) body mass index; medical therapy with (2) ACE inhibitors, (3) -blockers, or -blockers, or (4) calcium inhibitors; (5) wine intake; (6) tobacco use; (7) EPA in granulocytes [EPA(g)]; (8) DHA in(4) calcium inhibitors; (5) wine intake; (6) tobacco use; (7) EPA in granulocytes [EPA(g)]; (8) DHA in granulocytes [DHA(g)]; (9) total n=3 PUFAs in granulocytes [PUFA(g)]; (10) EPA in adipose granulocytes [DHA(g)]; (9) total n=3 PUFAs in granulocytes [PUFA(g)]; (10) EPA in adipose tissue[EPA(a)]; (11) DHA in adipose tissue [DHA(a)]; and (12) total n=3 PUFAs in adipose tissue tissue[EPA(a)]; (11) DHA in adipose tissue [DHA(a)]; and (12) total n=3 PUFAs in adipose tissue [PUFA(a)]. Nonmodifiable factors included in the test were (13) age, (14) left ventricular ejection [PUFA(a)]. Nonmodifiable factors included in the test were (13) age, (14) left ventricular ejection fraction, (15) previous MI, (16) sex, and (17) the extent of coronary artery disease. Significant fraction, (15) previous MI, (16) sex, and (17) the extent of coronary artery disease. Significant independent factors are given.independent factors are given.

Cirkulation 2001; 103: 651-7

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