Effect of dietary supplementation with v-3 fatty acids on progression of atherosclerosis in carotid arteries

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1 Crdiovsculr Reserch 54 (2002) locte/ crdiores Effect of dietry supplementtion with v-3 ftty cids on progression of therosclerosis in crotid rteries Peter Angerer *, Wolfgng Kothny, Stefn Stork, Clemens von Schcky Klinikum der Universitt Munchen, Institut und Poliklinik f ur Arbeits- und Umweltmedizin Innenstdt, Ziemssenstrsse 1, D Munchen, Germny Received 28 August 2001; ccepted 17 December 2001 Abstrct Objective: Omeg-3 polyunsturted ftty cids (v-3 PUFA) from fish oil slow therosclerosis progression in coronry rteries, s we showed in rndomized double-blind plcebo-controlled clinicl tril. Embedded in this tril, the present study exmined the influence of 2 yers of dietry supplementtion with 1.65 g v-3 PUFA per dy on progression of crotid therosclerosis in 223 ptients with coronry rtery disese. Methods: Coronry ngiogrphy, comprehensive clinicl exmintion, nd intim-medi thickness mesurement by B-mode ultrsound of the crotid rteries (common, internl nd bifurction), were performed t the study strt nd study end. An expert pnel visully evluted the globl chnge of crotid therosclerosis on semiquntittive scle. A second outcome mesure ws the chnge of overll men mximum intim-medi thickness. Results: One hundred nd seventy-one ptients completed the study. In the globl chnge score, 38% of the ptients in the fish oil group nd 35% in the plcebo group showed progression. Globl chnge ws not different between intervention groups. Men mximum intim-medi thickness incresed by mm nd mm in the fish oil nd plcebo group, respectively (men6s.d., P50.24). No correltion ws found between the chnge in crotid nd coronry rteries. Conclusions: In this group of selected ptients with documented coronry rtery disese v-3 PUFA given for 2 yers did not demonstrte n effect on slowing progression of therosclerosis in crotid rteries s mesured by ultrsound Elsevier Science B.V. All rights reserved. Keywords: Arteries; Atherosclerosis; Cerebrovsculr disorders; Lipid metbolism; Ultrsound 1. Introduction [3,4] or n inverse reltionship [5 7]. The Gruppo Itlino per lo Studio dell Soprvivenz nell Infrto miocrdico- An ssocition between high fish intke nd high Prevenzione (GISSI-P) tril clerly demonstrted reincidence of stroke, minly of the hemorrhgic subtype, duced mortlity in ptients with recent cute myocrdil ws observed in erly epidemiologicl studies, compring infrction who were treted by low dose v-3 PUFA; Greenlnd Inuit to the Dnish popultion [1,2]. This my however, no chnge in the risk for stroke, secondry be one reson why s yet no rndomized tril hs been end-point, ws observed [8]. undertken with the primry objective to clrify the effect Crotid rtery intim-medi thickness (IMT) predicts of v-3 polyunsturted ftty cids (v-3 PUFA) on cerebrl stroke [9,10]. Stenosis of internl crotid rteries with rteries or stroke. Menwhile severl lrge-scle epi-.60% lumen nrrowing plys cusl role for lrge demiologicl studies in Western popultions hve either percentge of strokes [11]. In ddition, progression in found no ssocition between fish consumption nd stroke crotid IMT predicts risk for coronry events beyond tht predicted by coronry rteril mesures of therosclerosis [12]. Crotid IMT mesured by ultrsound on the wll fr *Corresponding uthor. Tel.: ; fx: from the probe reflects the therosclerotic chnges detected E-mil ddress: peter.ngerer@rbeits.med.uni-muenchen.de (P. Angerer). Time for primry review 22 dys / 02/ $ see front mtter 2002 Elsevier Science B.V. All rights reserved. PII: S (02)

2 184 P. Angerer et l. / Crdiovsculr Reserch 54 (2002) tion conformed with the principles outlined in the Declr- tion of Helsinki. by utopsy [13]. Thus, complementry to the informtion bout the vessel lumen obtined by ngiogrphy IMT provides informtion bout the vessel wll. In the Study on Prevention of Coronry Atherosclerosis by Intervention with Mrine Omeg-3 Ftty Acids (SCIMO) we hve shown tht v-3 PUFA slow progression of therosclerosis in coronry rteries [14]. The study on which we report here investigted the effect of v-3 PUFA on progression of crotid rtery IMT. We hypothesized tht in ptients with coronry rtery disese (CAD) dietry supplementtion with 1.65 g/ dy eicospentenoic cid (EPA) nd docoshexenoic cid (DHA) for 2 yers would slow the progressive thickening of the intim-medi lyer in the crotid rteries Intervention Ptients were rndomized to fish oil or plcebo to be ingested in opque, identicl-looking nd -smelling, soft geltine cpsules. Ech cpsule contined 1 g of ftty cid mixture. During the first 3 months, six cpsules, corresponding to n intke of 3.3 g v-3 PUFA (EPA plus DHA) per dy, nd in the following 21 months, three cpsules, corresponding to n intke of 1.65 g v-3 PUFA (EPA plus DHA) per dy, were dvised. The plcebo group received mixture of ftty cids reflecting the ftty cid composition of the verge Europen diet. Further detils of the tretment hve been reported [14]. Overweight 2 2. Methods ptients (body mss index.25 kg/m ) were dvised to restrict their cloric intke, nd ll ptients were dvised to 2.1. Study design void cholesterol-rich food. Other dietry dvice ws not given. Medicl tretment ws dvised ccording to current The tril on the effect of v-3 PUFA on crotid thero- guidelines. Decisions concerning tretment were minly up sclerosis ws embedded in SCIMO, which hs been to the ptients personl physicin. reported in detil previously [14]. In brief, SCIMO ws Complince ws ssessed by interrogtion, by counting rndomized prospective, double-blind 2-yer intervention returned cpsules nd by nlysis of red cell phospholipid tril, conducted in ccordnce with the Europen Guide- ftty cid composition which reflects dietry ftty cid lines for Good Clinicl Prctice (GCP) in one medicl composition [14 16]. Ptients, whose cpsule count sugcenter of tertiry cre university hospitl. GCP requires gested ingestion of less thn 1658 cpsules, ($2 S.Ds from mong others regulr monitoring by n independent exter- the men), were considered non-complint. Ptients whose nl institution. Primry end-point of the present study ws percentge of EPA in red cell phospholipid ftty cids the chnge of therosclerosis in crotid rteries s ex- differed, ($2 S.Ds from the men of the respective pressed by globl chnge score per ptient in n tretment group), were lso considered non-complint. intention-to-tret nlysis. This end-point ws chosen s Non-complint ptients were excluded from the vlid cse primry by nlogy with the coronry study [14] where the nlysis. chnge of severity of CAD s ssessed by n expert pnel The rndomiztion list ws computer-generted by the on scle (see below) ws the primry end-point. Sec- tril monitor in Norwy nd the mediction ws prepred, ondry end-point ws the chnge of the overll men encoded, nd sent from there [14]. All ptients, study mximum IMT per ptient. personnel in contct with ptients, nd nlyticl personnel, were blinded with respect to study mediction. In 2.2. Ptients order to ensure blindness, ptients were told tht the All ptients who hd dignostic coronry ngiogrphy t our institution between September 1, 1992, nd My 19, 1994 were eligible if they hd.20% stenosis in $ Mesurements coronry vessel unless t lest one of the following contents of cpsules were differing in composition but not necessrily in tste. exclusion criteri ws present: revsculriztion by per- At study strt, fter the dignostic coronry ngiogrphy cutneous coronry intervention or coronry bypss oper- hd been performed, the clinicl sttus ws determined by tion plnned or performed in the preceeding 6 months in the investigtors. Cse report forms were then filled out more thn one vessel; crdic trnsplnttion; ge under 18 with predefined criteri reltive to history nd clinicl or over 75 yers; hemodynmiclly relevnt left min exmintion. Blood lbortory work-ups including 38 stenosis or proximl stenosis in ll three min vessels; routine prmeters plus erythrocyte phospholipid ftty cid biplne left ventriculr ejection frction below 35%; composition, resting electrocrdiogrm (ECG), nd n dibetes; nd others [14]. Written informed consent ws exercise stress test were obtined. Ptients were seen s obtined from ll ptients prior to rndomiztion. The outptients t months 1, 6, 12, 18. At ech visit, history, study ws pproved by the internl review bord of the clinicl sttus, nd the complete lbortory work-up were Ethics Committee of the Fculty of Medicine of the repeted. At month 24, ll investigtions were repeted, Ludwig-Mximilins-University of Munich. The investig- including coronry ngiogrphy during 2-dy hospitl

3 P. Angerer et l. / Crdiovsculr Reserch 54 (2002) sty. At month 0 nd 24, but not t months 1, 6, 12, 18, men of ll IMT mesurements (mximum of six fr wll blood ws tken fter n overnight fst. Low density mesurements) per ptient nd per point of time ws lipoprotein-cholesterol (LDL) ws clculted ccording to defined s overll men mximum IMT. The men of left the Friedewld formul. Myocrdil infrction, neurologic nd right side per segment, ptient, nd point of time ws deficits (ischemic or hemorrhgic), hypertension, nd defined s the men mximum IMT of the common nd dibetes mellitus were defined ccording to World Helth internl crotid rtery nd the crotid bifurction. Finlly, Orgniztion [17]. by directly compring the imges, the experts decided The evlution process of the coronry ngiogrms hs whether segment hd chnged. At the beginning, they been reported previously [14]. In brief, three crdiologists worked seprtely, nd eventully reched consensus for who were blinded to ll spects which might identify the ech segment. After the file hd been closed, ech segcoronry ngiogrms evluted the films, pirwise per ment s chnge ws identified s progression or regression, ptient, determined the lumen nrrowing for ech prt of ccording to the temporl order of the films. The globl the coronry tree, then firstly rted ech single chnge nd chnge ws obtined by summing up the chnges for ech eventully the overll chnge of the ngiogrms on scle segment per ptient. Thus score resulted rnging from termed globl chnge score. Of the seven possible scores 26 to16 including 0. This method ws dpted from both extreme vlues (extreme progression nd regression) coronry ngiogrphy trils nd modified ccording to the did not occur, resulting in score with five ctegories [14]. conditions of ultrsound imges [14,19]. Reproducibility ws ssessed by repeting ultrsound 2.5. Crotid ultrsound exmintion either within 1 month of the exmintion t study strt or t study end in rndomly selected subsm- Ultrsound exmintion of the crotid rteries ws ple of 33 ptients. The correltion coefficient between the performed by the sme investigtor t the study strt nd first nd second mesurement ws r The men study end, ccording to the identicl protocol nd using the difference of the overll men mximum IMT nd its S.D. sme high resolution ultrsound unit with 7.5 MHz were used s mesures of reproducibility [20], nd were sector scnner with Doppler fcility (Alok SSD 620, mm. Jpn). Instrument performnce ws checked regulrly by mens of n RMI 413 tissue mimicking phntom. Ptients 2.6. Sttisticl nlysis rested supine in semi-drkened, ir-conditioned room with smll pillow under their neck. Three ntomiclly The estimtion of study size hs been described previpredefined segments were exmined: the distl 20 mm of ously [14]. In brief, bsed on the ssumption tht v-3 the common crotid rtery, the crotid bifurction, nd the PUFA would slow progression of crotid therosclerosis s proximl 10 mm of the internl crotid rtery, on both ssumed for coronry therosclerosis, with n of 5% nd sides of the neck (i.e. six segments in totl). Firstly, the b of 10%, nd drop-out rte of 33%, inclusion of 97 entire circumference of ech segment ws scnned s fr ptients per group (73 ptients per group for the nlysis) s possible in order to detect ny hemodynmiclly ws necessry. In the present tril we used n lmost relevnt stenosis. Then, three ngles of interrogtion were identicl score s the primry end-point, which differed used: oblique nterior (1458), lterl (08) nd oblique only from the coronry end-point in tht it contined more posterior (2458). The optiml longitudinl view with subdivisions. In ddition, numericl mesurement (IMT) cler imge of interfces between lumen, intim-medi, ws used. Both dpttions re expected to increse power. nd dventiti ws 2-fold mgnified nd recorded on video Therefore it ws estimted tht the smple size of SCIMO nd high resolution X-ry film. would llow us to detect relevnt tretment effect lso in For evlution, only imges of the fr wll were used the crotid rteries. since mesurements of the ner wll underestimte the true In order to compre chnges of coronry rteries with histologicl thickness [13,18]. An expert pnel of two chnges of crotid rteries, the chnge score of crotid experienced sonogrphers evluted the films, pired (be- rteries ws modified, i.e. reduced to contin lso only five fore nd fter tretment) per ptient, but in rndom order, (insted of originlly 13) ctegories. This ws done by nd blinded with respect to ll ptient chrcteristics like integrting ( collpsing ) scores.2 nd,22 into score 2 nme, rndomiztion sttus, nd temporl order of films. nd 22, respectively. We termed the resulting score for the They first decided whether segment ws documented in crotid rteries modified score. sufficient qulity t both points of time, t lest from one All dt were entered into the study computers twice ngle of interrogtion. Then they mesured the mximum independently, using Dt Entry (SPSS, USA), verified, IMT per segment, to get two bsolute vlues of IMT, on nd copy of ll relevnt dt ws deposited t the tril the digitized imges, by mens of the softwre NIH-Imge monitor in Norwy. After confirmtion of receipt, the (Ntionl Institutes of Helth, USA), on Power Mcin- rndomiztion code ws broken, nd dt processed on tosh 8100/ 80 with high resolution screen. Ech mesure- Power Mc 7600/ 120 (Apple, USA) using the softwre ment ws performed twice nd the results verged. The SPSS in version 6.0 for the Mcintosh. Student s t-test,

4 186 P. Angerer et l. / Crdiovsculr Reserch 54 (2002) chi nd Wilcoxon s rnk sum tests were used ccording to the nture of the vribles. potentil influence on crotid therosclerosis were not significntly different in the fish oil group compred to the plcebo group (Tble 2). However, EPA nd DHA in the erythrocyte membrne incresed in the fish oil group 3. Results within the first month (not shown) nd styed stble therefter, wheres ftty cid composition did not chnge Of 2284 ptients screened, 112 nd 111 were rndom- in the plcebo group (Tble 2). ized to fish oil nd plcebo, respectively. After 2 yers, 89 Repeted ssessment (score nd IMT mesurement) ptients in the fish oil group nd 86 ptients in the plcebo could be performed t men number of 5.3 (of mximum group hd complete clinicl follow-up. Of these, 87 six) segments per ptient. By expert pnel evlution, ptients with fish oil nd 84 ptients with plcebo hd 37.8% of ptients in the fish oil group nd 34.5% in the second ultrsound exmintion in the required qulity plcebo group were rted to show progression of crotid (intention to tret popultion). Sequentil coronry ngiog- therosclerosis fter 2 yers. The globl score ws not rms were performed in 159 of these subjects (in three different in the fish oil group compred with the plcebo subjects coronry ngiogrms but not crotid exmintions group (Tble 3). During follow-up, overll men mxiwere complete before nd fter intervention). Eventully, mum IMT per ptient incresed by mm nd 80 ptients with fish oil nd 78 ptients with plcebo mm in the fish oil nd plcebo group, respecfulfilled the criteri for complince (vlid cse popultion). tively (men6s.d., P50.24). Increse of IMT ws lso (Tril profile see Fig. 1). slightly greter in the fish oil group when the chnge of Rndomiztion ws successful with respect to ll ech of the segments ws nlysed seprtely (common chrcteristics relevnt for the primry end-point (Tble nd internl crotid rtery nd crotid bifurction) (Tble 1). During follow-up, chnges in chrcteristics with 4). Exclusion of non-complint ptients (vlid cse nly- Fig. 1. Tril profile.

5 P. Angerer et l. / Crdiovsculr Reserch 54 (2002) Tble 1 Bseline chrcteristics of ll ptients with complete ultrsound follow-up by tretment group Fish oil (n587) Plcebo (n584) Age (yers) Mle 72 (82.8%) 69 (82.1%) Prior myocrdil infrction 43 (49.4%) 47 (55.9%) Prior TIA 2 (2.3%) 1 (1.2%) Prior PRIND 1 (1.1%) 0 Prior ischemic stroke 1 (1.1%) 2 (2.4%) Current smokers 9 (10.3%) 17 (20.2%) Dignosis of systemic hypertension 45 (51.7%) 37 (44.1%) Fmily history of premture myocrdil infrction 20 (23.0%) 27 (32.1%) LDL-cholesterol (mmol/ l) HDL-cholesterol (mmol/ l) Triglycerides (mmol/ l) Number of min coronry vessel with stenosis $70% Number of coronry segments with stenosis $50% Crotid rteries: men mximum IMT (mm) Common crotid rtery: men mximum IMT (mm) Crotid bifurction: men mximum IMT (mm) Internl crotid rtery: men mximum IMT (mm) Figures indicte: men6s.d. or bsolute number (%). t-test or chi -test; ll P.0.25 except for the following. 2 chi, n.s. (P50.072). were complete for 159 ptients. There ws no correltion between the two scores in the entire popultion (Sper- mn s coefficient, r520.04, P50.67) nd no correltion when the fish oil nd the plcebo group were nlysed seprtely. 4. Discussion In this rndomized controlled double-blind tril, ptients with CAD received dietry supplementtion with 1.65 g sis) yielded lmost identicl results for chnge of globl score nd chnge of men mximum IMT (dt not shown). No stroke or prolonged reversible ischemic neurologic deficit occurred during the study. Of the 175 ptients with complete clinicl follow-up, one ptient in the fish oil group nd three ptients in the plcebo group reported symptoms tht were rted s trnsient ischemic ttck. Dt for the nlysis of correltion between the modified globl chnge score of the crotid rteries (five ctegories) nd the coronry globl chnge score (five ctegories) Tble 2 Potentil influences on crotid therosclerosis during 24 months follow-up by tretment group Fish oil (n587) Plcebo (n584) Number of ptients on spirin 85 (97.7%) 82 (97.6) Number of ptients on lipid lowering gents 40 (47.6) 43 (53.1) Number of ptients on ACE inhibitors 31 (36.0%) 23 (28.4%) Number of ptients on bet-blockers 68 (78.2%) 69 (82.1%) Number of ptients smoking t follow-up 12 (13.4%) 13 (15.7%) Chnge in LDL-cholesterol (mmol/ l) Chnge in HDL-cholesterol (mmol/ l) b Chnge in triglycerides (mmol/ l) Chnge in systolic blood pressure (mmhg) Chnge in distolic blood pressure (mmhg) Chnge of eicospentenoic cid in erythrocyte membrne (percent points) c c Chnge of docoshexenoic cid in erythrocyte membrne (percent points) d d Figures indicte: men6s.d. or bsolute number (%). t-test or chi -test; ll P.0.25 except for the following: t-test, n.s. (P50.073). b t-test, n.s. (P50.20). c t-test, P, d t-test, P

6 188 P. Angerer et l. / Crdiovsculr Reserch 54 (2002) Tble 3 therogenic effect of v-3 PUFA is specific for certin Chnge of crotid therosclerosis per ptient within 24 months follow-up vsculr beds such s the coronry circultion, or tht this s evluted by expert pnel effect is t lest mterilly smller in crotid thn in Fish oil Plcebo coronry rteries. Compred to myocrdil infrction, n587 n584 stroke usully occurs in ptients t much older ge. This Men number of sites compred indictes tht the cerebrl vsculr bed is ffected t different pce. Moreover, the reltive importnce of risk Number of ptients with: Score 22 (regression) 1 (1.1%) 0 fctors on therosclerosis progression seems to vry for the Score 21 (regression) 1 (1.1%) 5 (6%) cerebrl nd the coronry circultion, e.g., there is lower Score 0 (no chnge) 52 (59.8%) 50 (59.5%) impct of hyperlipidemi on the first compred to the ltter Score 1 (progression) 25 (28.7%) 18 (21.4%) [29]. Score 2 (progression) 6 (6.9%) 9 (10.7%) In the present study, the bsence of correltion Score 3 (progression) 1 (1.1%) 2 (2.4%) Score 4 (progression) 1 (1.1%) 0 between chnge of crotid rtery wll thickness ssessed by ultrsound nd coronry lumen nrrowing ssessed by Figures indicte: number (%). ngiogrphy, emphsizes tht both methods exmine dif Wilcoxon, n.s. (P50.62). ferent spects of the sme disese nd tht these spects my be influenced by interventions in specific wy. v-3-pufa per dy (EPA plus DHA) or plcebo, for 2 These findings lso suggest tht the effect of ny intervenyers, in ddition to stndrd tretment. Active tretment tion on crotid IMT must be interpreted with cution. did not slow progression of crotid therosclerosis. Chnge One epidemiologicl study exmined the reltionship of therosclerosis in crotid rteries nd in coronry between intke of fish nd v-3 PUFA nd the risk of rteries in these ptients during the sme period were not stroke by stroke subtype [7]. The ssocition of fish intke correlted. with reduced risk of thrombotic infrction ws due to Previously we hve shown tht v-3 PUFA mitigte reduced risk in lcunr (smll cerebrl) rtery but not in progression of therosclerosis in coronry rteries of lrge (crotid) rtery occlusive infrction [7]. Of note, the ptients with CAD [14]. Occlusion of venous orto corinverse ssocition between v-3 PUFA intke nd stroke onry bypss grfts occurred less frequently when ptients ws not observed in the subgroup on spirin mediction were treted with v-3 PUFA for 1 yer compred to [7]. In our study, more thn 97% of the ptients were on plcebo [21]. Experimentl studies in dog, swine nd tretment with spirin. Thus, if fvorbly ltered pltelet non-humn primtes, demonstrted reduction of the function nd hemostsis explins some of the effects of therosclerotic nrrowing of the rteril lumen by dietry v-3 PUFA [30], tretment with spirin which strongly v-3-pufa [22]. DHA nd EHA influence the therosffects pltelet ggregtion might hve obscured these clerotic process by severl mechnisms [23,24]. They effects. Moreover, the beneficil impct of v-3 PUFA on intervene in erly stges of therogenesis, e.g., by specific endothelil function of smll rteries [31], endothelil downregultion of gene expression for PDGF-A, PDGF-B, modultion [32], rteril complince [33], blood viscosity nd MCP-1 [25]. Epidemiologicl studies demonstrted n [34], inflmmtion [35], blood pressure [36], shift in the inverse correltion between fish consumption nd incident eicosnoid system towrds nti-ggregtion nd vsodiltnon-ftl myocrdil infrction [1,26,27]. Recently, this ion [23], nd other mechnisms [24] lone or in concert, hs been confirmed by 30-yer follow-up in men who my reduce risk for vsculr disese morbidity nd morwere free of overt crdiovsculr disese t bseline nd tlity. Thus, we consider the lck of n effect on crotid who consumed $35 g fish per dy [28]. In this context, therosclerosis not contrdictory to the beneficil clinicl our present negtive finding suggests tht the ntieffect found in other studies. Our study ws not powered to detect differences in morbidity nd mortlity. Yet, one TIA Tble 4 nd three TIAs in the fish oil nd plcebo-treted groups Absolute chnge of IMT in crotid rtery fr wlls during 24 months were observed. Possibly, study including ptients with follow-up by tretment group substntilly higher risk for cerebrovsculr events (or Fish oil Plcebo much lrger study) would be ble to clrify the issue of n587 n584 risk reduction for stroke. Men number of sites compred Severl issues must be discussed tht potentilly limit Overll men mximum IMT (mm) our conclusions. The nnul progression of crotid IMT Common crotid men mximum IMT (mm) b ws smller thn in nother study which included ptients Bifurction men mximum IMT (mm) Internl crotid men mximum IMT (mm) with CAD, n IMT of $1.3 mm, nd elevted cholesterol [37], but it ws comprble to tht of more helthy Figures indicte: men6s.d. t-test; ll P.0.25 except for the followpopultion with elevted LDL [38]. This my be due to the ing. t-test, n.s. (P50.24). medicl tretment ptients received (see Tble 2), especil- b t-test, n.s. (P50.12). ly the use of lipid lowering drugs in hlf of the ptients t

7 P. Angerer et l. / Crdiovsculr Reserch 54 (2002) some time during the study. This represents the stndrd Gesellschft fur Strhlenforschung (GSF, 07ERG03) nd sitution for ptients with high risk for coronry or Deutsche Forschungsnstlt fur Luft- und Rumfhrt cerebrovsculr events. We observed n increse of blood (DLR, 01 EA 9501/ 7), nd Wilhelm Snder-Stiftung pressure in both the fish oil nd the plcebo group. At the (93.032). Other support ws from Fundcion Federico nd study strt nd during the follow-up the identicl protocol the Deutsche Forschungsgemeinschft (Sch 398). for mesuring blood pressure ws used. Yet, wheres t the Pronov, A.S., Lysker, Norwy provided the cpsules, study strt ptients underwent hert ctheteriztion due to nd funds for monitoring. n cute medicl problem, the mjority of them ws reltively well during follow-up. As consequence of the well-being, there is possibility tht (non-reported) complince References with mediction other thn the study mediction deteriorted during the study. In ddition, the reported use [1] Kromnn N, Green A. Epidemiologicl studies in the Upernvik of bet-blockers decresed nd the body mss index district, Greenlnd. Incidence of some chronic diseses Act Med Scnd 1980;208: incresed. Reproducibility of the crotid IMT mesure- [2] Ostergrd Kristensen M. Incresed incidence of bleeding intrcrnments in this study is within the rnge of severl other il neurysms in Greenlndic Eskimos. Act Neurochir (Wien) trils which published the respective dt [39]. Since the 1983;67: effect of fish oil on therosclerosis progression in coronry [3] Morris MC, Mnson JE, Rosner B et l. Fish consumption nd circultion in the min study ws smller thn expected, crdiovsculr disese in the physicins helth study: prospective study. Am J Epidemiol 1995;142: we performed secondry power estimtion for the present [4] Orenci AJ, Dviglus ML, Dyer AR, Shekelle RB, Stmler J. Fish study. It showed tht miniml difference of 0.02 mm in consumption nd stroke in men. 30-yer findings of the Chicgo the nnul progression rte between tretment groups ws Western Electric Study. Stroke 1996;27: detectble with power of 80%. Thus, it is possible tht [5] Keli SO, Feskens EJ, Kromhout D. Fish consumption nd risk of we missed smll effect. Yet, s the IMT progression rte stroke. The Zutphen Study. Stroke 1994;25: [6] Gillum RF, Mussolino ME, Mdns JH. The reltionship between in the fish oil group ws even slightly higher nd the fish consumption nd stroke incidence. The NHANES I Epiglobl score ws lmost identicl in both intervention demiologic Follow-up Study (Ntionl Helth nd Nutrition Exmigroups, the risk for this type of error is smll. A review of ntion Survey). Arch Intern Med 1996;156: epidemiologicl nd intervention studies suggests tht 0.5 [7] Iso H, Rexrode KM, Stmpfer MJ et l. Intke of fish nd omeg-3 to 2.0 g v-3 PUFA per dy re effective in reducing ftty cids nd risk of stroke in women. J Am Med Assoc 2001;285: clinicl end-points [24]. By contrst, higher doses yielded [8] Gruppo Itlino per lo Studio dell Soprvvivenz nell Infrto no effect [40]. Thus, we would not expect stronger effect miocrdico. Dietry supplementtion with n-3 polyunsturted ftty with higher doses. Blinding my be problem in studies cids nd vitmin E fter myocrdil infrction: results of the using fish oil becuse of the intense tste of the encpsuled GISSI-Prevenzione tril. Lncet 1999;354: content. As shown previously [14], ptients guess on wht [9] Bots ML, Hoes AW, Koudstl PJ, Hofmn A, Grobbee DE. Common crotid intim-medi thickness nd risk of stroke nd they hd received ws not significntly different between myocrdil infrction: the Rotterdm Study. Circultion groups, nd the mjority of ptients (70% on fish oil, 76% 1997;96: on plcebo in the present study) ws undecided. [10] O Lery DH, Polk JF, Kronml RA et l. Crotid rtery intim nd In conclusion, the present rndomized tril imed t medi thickness s risk fctor for myocrdil infrction nd stroke exploring whether v-3 PUFA from fish oil could benefi- in older dults. Crdiovsculr Helth Study Collbortive Reserch Group. New Engl J Med 1999;340: cilly influence crotid therosclerosis. The evlution ws [11] Brnett HJ, Gunton RW, Elisziw M et l. Cuses nd severity of bsed on ultrsound mesurements of IMT nd for globl ischemic stroke in ptients with internl crotid rtery stenosis. J scoring of the chnge of crotid vessel wll. In our ptients Am Med Assoc 2000;283: with coronry rtery disese, v-3 PUFA given over 2 yers [12] Hodis HN, Mck WJ, LBree L et l. The role of crotid rteril in dose shown to be effective for coronry rteries did intim-medi thickness in predicting clinicl coronry events. Ann Intern Med 1998;128: not slow progression of therosclerosis of the crotid [13] Wong M, Edelstein J, Wollmn J, Bond MG. Ultrsonic-pthologicl rteries compred to conventionl tretment. Due to the comprison of the humn rteril wll. Verifiction of intim-medi power of the study smll beneficil effect could hve thickness. Arterioscler Thromb 1993;13: been missed. However, in the context of other epieffect [14] von Schcky C, Angerer P, Kothny W, Theisen K, Mudr H. The of dietry omeg-3 ftty cids on coronry therosclerosis. A demiologicl nd rndomized trils our dt indicte tht rndomized, double-blind, plcebo-controlled tril. Ann Intern Med in ptients with CAD v-3 PUFA do not substntilly slow 1999;130: crotid therosclerosis. [15] von Schcky C, Fischer S, Weber PC. Long-term effects of dietry mrine omeg-3 ftty cids upon plsm nd cellulr lipids, pltelet function, nd eicosnoid formtion in humns. J Clin Invest Acknowledgements 1985;76: [16] Siscovick DS, Rghunthn TE, King I et l. Dietry intke nd cell Supported in lrge prts by the Bundesministerium fur membrne levels of long-chin n-3 polyunsturted ftty cids nd the risk of primry crdic rrest. J Am Med Assoc 1995;274:1363 Forschung und Technologie, Germny, through 1367.

8 190 P. Angerer et l. / Crdiovsculr Reserch 54 (2002) [17] Rose GA, Blckburn H, Gillum RF, Prines RJ. Crdiovsculr 30-yer risk of ftl myocrdil infrction. New Engl J Med survey methods. Genev: World Helth Orgniztion, ;336: [18] Wendelhg I, Gustvsson T, Suurkul M, Berglund G, Wikstrnd J. [29] Ingll TJ. Preventing ischemic stroke. Postgrd Med 2000;107:34 Ultrsound mesurement of wll thickness in the crotid rtery: 50. fundmentl principles nd description of computerized nlysing [30] Knpp HR. Dietry ftty cids in humn thrombosis nd hemostsis. system. Clin Physiol 1991;11: Am J Clin Nutr 1997;65:1687S 1698S. [19] Blnkenhorn DH, Selzer RH, Mck WJ et l. Evlution of [31] Goode GK, Grci S, Hegerty AM. Dietry supplementtion with colestipol/ nicin therpy with computer-derived coronry end point mrine fish oil improves in vitro smll rtery endothelil function in mesures. A comprison of different mesures of tretment effect. hypercholesterolemic ptients: double-blind plcebo-controlled Circultion 1992;86: study. Circultion 1997;96: [20] Blnd JM, Altmn DG. Sttisticl methods for ssessing greement [32] De Cterin R, Lio JK, Libby P. Ftty cid modultion of between two methods of clinicl mesurement. Lncet 1986;1:307 endothelil ctivtion. Am J Clin Nutr 2000;71:213S 223S [33] McVeigh GE, Brennn GM, Cohn JN et l. Fish oil improves rteril [21] Eritslnd J, Arnesen H, Gronseth K, Fjeld NB, Abdelnoor M. Effect complince in non-insulin-dependent dibetes mellitus. Arterioscler of dietry supplementtion with n-3 ftty cids on coronry rtery Thromb 1994;14: bypss grft ptency. Am J Crdiol 1996;77: [34] Woodcock BE, Smith E, Lmbert WH et l. Beneficil effect of fish [22] Sssen LM, Lmers JM, Verdouw PD. Fish oil nd the prevention oil on blood viscosity in peripherl vsculr disese. Br Med J (Clin nd regression of therosclerosis. Crdiovsc Drugs Ther Res Ed) 1984;288: ;8: [35] Endres S, von Schcky C. n-3 polyunsturted ftty cids nd [23] von Schcky C. Prophylxis of therosclerosis with mrine omeg-3 humn cytokine synthesis. Curr Opin Lipidol 1996;7: ftty cids comprehensive strtegy. Ann Int Med [36] Morris MC, Scks F, Rosner B. Does fish oil lower blood pressure? 1987;107: A met-nlysis of controlled trils. Circultion 1993;88: [24] Angerer P, von Schcky C. n-3 polyunsturted ftty cids nd the [37] Crouse JRR, Byington RP, Bond MG et l. Prvsttin, Lipids, nd crdiovsculr system. Curr Opin Lipidol 2000;11: Atherosclerosis in the Crotid Arteries (PLAC-II). Am J Crdiol [25] Bumnn KH, Hessel F, Lrss I et l. Dietry omeg-3, omeg-6, 1995;75: nd omeg-9 unsturted ftty cids nd growth fctor nd cytokine [38] Slonen R, Nyyssonen K, Porkkl E et l. Kuopio Atherosclerosis gene expression in unstimulted nd stimulted monocytes. A Prevention Study (KAPS). A popultion-bsed primry preventive rndomized volunteer study. Arterioscler Thromb Vsc Biol tril of the effect of LDL lowering on therosclerotic progression in 1999;19: crotid nd femorl rteries. Circultion 1995;92: [26] Bng HO, Dyerberg J. Plsm lipids nd lipoproteins in Greenlndic [39] Knters SD, Algr A, vn Leeuwen MS, Bng JD. Reproducibility west cost Eskimos. Act Med Scnd 1972;192: of in vivo crotid intim-medi thickness mesurements: review. [27] Miettinen TA, Nukkrinen V, Huttunen JK, Mttil S, Kumlin T. Stroke 1997;28: Ftty-cid composition of serum lipids predicts myocrdil infrc- [40] Scks FM, Stone PH, Gibson CM et l. Controlled tril of fish oil tion. Br Med J (Clin Res Ed) 1982;285: for regression of humn coronry therosclerosis. HARP Reserch [28] Dviglus ML, Stmler J, Orenci AJ et l. Fish consumption nd the Group. J Am Coll Crdiol 1995;25: