Coagulation Factor VII in Elderly People: Genetic Disposition and Diet. Louise Mennen

Transcription

1 Cagulatin Factr VII in Elderly Peple: Genetic Dispsitin and Diet Luise Mennen

2 Prmtren: Dr. ir. F.J. Kk Hgleraar in de Humane Epidemilgic Dr. D.E. Grbbee Hgleraar in de Klinische Epidemilgic C-prmtr: Dr. E.G. Schuten Universitair hfddcent bij de Afdeling Humane Veding en Epidemilgic

3 ^ t^^^\,23ij Luise Ingebrg Mennen Cagulatin Factr VII in Elderly Peple: Genetic Dispsitin and Diet Prefschrift ter verkrijging van de graad van dctr p gezag van de rectr magnificus van de Landbuwuniversiteit te Wageningen, dr. CM. Karssen, in het penbaar te verdedigen p wensdag 17 September 1997 des namiddags te vier uur in de Aula "N

4 The studies presented in this thesis were supprted by a grant frm the Netherlands Organizatin fr Scientific Research (NWO) (N ). The Rtterdam Study is supprted by the NESTOR Prgram fr Geriatric Research in the Netherlands (Ministry f Health and Ministry f Educatin). Additinal supprt is btained frm the Netherlands Organisatin fr Scientific Research (NWO), the Netherlands Preventin Fund, the Municipality f Rtterdam, the Netherlands Heart Fundatin, the Dutch Thrmbsis Fundatin, the Rtterdam Medical Research Fundatin, Tpcn Eurpe BV, Rtterdamse Vereniging vr Blindenbelangen, Stichting Bevrdering vr Vlkskracht, Stichting Fndsenwerving Acties Vlksgezndheid. The interventin study was supprted by Unilever Research Labratrium, Vlaardingen. Financial supprt by the Netherlands Organizatin fr Scientific Research and by the Julius Center fr Patient Oriented Research, Utrecht University Medical Schl, fr the publicatin f this thesis is gratefully acknwledged. CIP-DATA KONINKLIJKE BIBLIOTHEEK, DEN HAAG Mennen, L.I. Cagulatin factr VII in elderly peple: genetic dispsitin and diet/ L.I. Mennen. -[S.I.:s.n.]. Thesis Landbuw Universiteit Wageningen. -With ref- With summary in Dutch ISBN Subject headings: factr VII / diet / genetics / elderly peple Printing: Pnsen & Lijen BV Wageningen L.I. Mennen, Wageningen, the Netherlands BIBLIOTHEEK LANDBOUVv'l.'NTVERSnT- WAGKNINGF/N*

5 Never let a malignant dminant male destry yur "jie de vivre"! (J.G. van der Bm, Schiermnnikg, nvember 1994) This is nt Bird-science we 're talking here! (O.S. Miettinen, Schiermnnikg, nvember 1994) Aan mijn fantastische Ouders en mijn bijzndere Oma!

6 ABSTRACT Cagulatin factr VII in elderly peple: genetic dispsitin and diet PhD thesis by Luise I. Mennen, Divisin f Human Nutritin and Epidemilgy Wageningen Agricultural University, The Netherlands. September 17, 1997 In elderly peple an increase in thrmbtic tendency may lead t a increase in the risk f a crnary event. Cagulatin factr VII affects this thrmbtic tendency and has been recgnised as a risk indicatr fr crnary heart disease. It is nt knwn whether the level f factr VII can be influenced at lder age. Frm studies in yung subjects it is clear that dietary fat and the R/Q353 plymrphism (alleles R and Q) are the main determinants f factr VII. We studied the relatin f factr VII with diet in elderly men and wmen, taking the R/Q353 plymrphism int accunt. In a crss-sectinal study amng 1158 elderly men and wmen (>55 y) factr VII cagulant activity (FVII:C) and ttal factr VII (FVIIt) were investigated in relatin t serum-triglycerides, the R/Q353 plymrphism and the habitual diet. FVII:C was inversely assciated with dietary fibre and prtein and psitively with saturated fat intake and serum-triglycerides. These assciatins were much strnger in subjects with the RR gentype cmpared t thse carrying the Q allele; if the mean intake f dietary fibre wuld increase with 10 g a day, FVILC wuld be expected t decrease with 7.6 % in elderly peple hmzygus fr the R allele versus nly 1.9% decrease in thse carrying the Q allele. FVIIt was inversely related t intake f dietary fibre and psitively t serumtriglycerides, again the assciatins being strnger in subjects with the RR gentype. In a crss-ver study amng elderly wmen (> 60 y, 35 RQ/QQ, 56RR) the pstprandial respnse f activated factr VII (FVIIa) t several fat-rich (50 g) breakfasts was evaluated. The respnse f FVIIa was very similar fr meals rich in palmitic acid, rich in stearic acid r rich in linleic/linlenic acid with a rati f 3:1 r 15:1. The increase in FVIIa ranged frm 14.9 (95% CI:10.6,19.2) IU/mL after the stearic rich breakfast t 21.1 (16.6,25.6) IU/mL after the linleic/linlenic 15:1 rich breakfasts. After the fat-free cntrl breakfast FVIIa decreased with 8.7 (6.3,11.1) IU/mL. The mean abslute ttal respnse t the fatrich breakfasts cmbined was 37 IU/mL in subjects with the RR gentype and 16.1 IU/mL in subjects carrying the Q allele. Als the respnse relative t the fasting FVIIa level differed significantly between the gentype grups (RR: 42%, RQ/QQ: 32%). Serumtriglycerides cncentratin was nt assciated with FVIIa. In elderly peple, factr VII is influenced by dietary fibre, ttal dietary fat and serumtriglycerides and nt by fat type. The R/Q353 plymrphism strngly mdifies these effects. This indicates that an increase in dietary fibre and a decrease in dietary fat intake may reduce the risk f a crnary event by reducing the level f factr VII, particularly in elderly peple with the RR gentype.

7 CONTENTS Chapter 1 General Intrductin 11 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Cagulatin factr VII, dietary fat and bld lipids: a review 17 The assciatin f dietary fat and fibre with cagulatin factr VII in the elderly: The Rtterdam Study 33 Dietary effects n cagulatin factr VII vary acrss gentypes f the R/Q353 plymrphism 43 Cagulatin factr VII, serum-triglycerides and the R/Q353 plymrphism: differences between lder men and wmen 53 Factr Vila respnse t a fat-rich meal des nt depend n fatty acid cmpsitin: A randmized cntrlled trial 59 Pstprandial respnse f cagulatin factr Vila varies acrss R/Q353 gentypes 69 Chapter 8 General discussin 75 References 89 Summary 99 Samenvatting 105 Dankwrd 110 Curriculum Vitae 112

8 CHAPTER 1 General intrductin 11

9 Chapter 1 Cagulatin cascade Haemstasis is a defense mechanism that serves t prtect the integrity f the vascular system after injury f the endthelium f the vessel wall. The haemstatic prcess cnsists f platelet activatin, bld cagulatin and fibrinlysis. This system is nrmally quiescent but becmes active within secnds after injury. Tgether with platelet activatin, triggering f the cagulatin system results in the frmatin f a bld clt and cclusin f the injured site. The fibrinlytic system disslves the haemstatic plug in the curse f vessel healing and repair. If the balance between cagulatin and fibrinlysis is disturbed, extensive clt frmatin can take place, which may influence the develpment f cardivascular disease 1 " 4. The cagulatin system is a sequential activatin f certain plasma prteases (prenzymes) t their enzyme frms. This cascade f activatin reactins will finally lead t the frmatin f fibrin. The cagulatin system as such will be clarified in detail belw, but fr reasn f simplicity nt all inhibitrs r external factrs influencing the cascade are described. After injury, bld cagulatin is activated by the release f tissue factr frm the vessel wall (Figure 1.1). Tissue factr binds t factr VII and frms a cmplex with it. If factr VII is activated it will activate factr X t Xa and factr IX t IXa. Factr IXa will frm a cmplex with factr Villa and this cmplex is a secnd activatr f factr X 5. The prtease respnsible fr the initial activatin f factr VII is unknwn, but nce cltting is activated, several prteases further alng the pathway, like factr Xa and IXa, can in turn activate factr VII. This will lead t an acceleratin f the factr VII activatin. Althugh factr Vila is able t activate factr X, the activatin f factr X by IXa is the main rute, since the factr Vila/tissue factr cmplex will be rapidly inhibited by tissue factr pathway inhibitr (TFPI). Once thrmbin is frmed the activatin f factr XI is catalyzed. Once factr XIa is generated, there is an additinal mechanism fr augmenting the activatin f factr IX, which makes the factr Vll/tissue factr cmplex at that mment redundant fr the activatin f factr X. Factr Xa in cmplex with factr Va activates prthrmbin int thrmbin (factr Ila). Thrmbin cleaves fibringen int mnmeric fibrin, which then plymerizes t frm the fibrin clt. This whle prcess takes place n different cell-surface membranes, which play an imprtant rle in the frmatin f several cmplexes 5. In shrt the tissue factr/factr VII cmplex is needed t activate factr X and start the initial generatin f thrmbin, after which the activatin f factr IX and factr XI will result in an explsive frmatin f fibrin. 12

10 General intrductin Figure 1.1. The cagulatin cascade TFPI tissuefactr FVII -UFVIIa tt_ * r FlXa-^ FIX FXIa- FXI Flla FVHIaJ^-FVIII FX^ FXa FVa. Flla FV FN Flla (thrmbin) fibringen --fibrin Factr VII Factr VII is ne f the cagulatin factrs fund t be assciated with cardivascular disease 2 ' 6. Tw prspective studies have shwn that factr VII is higher in persns wh died frm crnary heart disease than in persns withut the disease 2,6. It is cnceivable that a small increase f FVIIa may lead t an extensive frmatin f fibrin and thereby increase the chance f a vessel cclusin after rupture f an athersclertic plaque. T increase understanding f the behaviur f factr VII in relatin t its determinants sme bichemical aspects f factr VII will be described. Factr VII is a single-chain glycprtein, with a mlecular weight f apprximately 50, This mature prtein is cmpsed f 406 amin acids 8. It is a vitamin K dependent cagulatin factr and has a high degree f hmlgy with factr II, IX, X, prtein C and prtein S. It is synthesized by the liver and secreted int the bld as an inactive zymgen. It has the mst rapid turnver rate f any cagulatin factr, with a half-life f 2 t 7 hurs after activatin 7. The single chain frm f factr VII as fund in plasma 13

11 Chapter 1 becmes activated (factr Vila) after enzymatic cleavage and has a 60- t 80-fld increased cagulant activity 7. Cleavage can be perfrmed by factr Xa, factr Xlla, factr IXa and thrmbin 8 " 10. This happens nrmally when the vessel wall is damaged and tissue factr is released, but als cld strage and cntact activatin with glass can activate factr VII zymgen 7. In each case, a single Arg He 153 internal bnd is cleaved, which results in the frmatin f a tw-chain active enzyme cmpsed f a light chain and a heavy chain held tgether by a disulphide bnd. Abut 1% f the ttal amunt f factr VII in the circulatin exists as activated factr VII, the ther part exists as the inactive factr VII zymgen. Several methds are available t measure factr VII. The activated part f factr VII can be measured directly (factr Vila), but als the cagulant activity f factr VII (factr VII:C) can be analyzed. Furthermre tw methds exist t measure the ttal amunt f factr VII (factr Vllt) in plasma. These methds will be described in mre detail in Chapter 2. Determinants f factr VII Factr VII increases with age and with use f ral anticnceptives r hrmne replacement therapy. It is psitively assciated with bdy mass index and is higher in wmen than in men especially after menpausal age"" 14. Furthermre, factr VII was fund t be assciated with bld pressure, alchl intake, smking, physical exercise and intake f caffeine"' 215 " 18, but these findings are nt cnsistent. The majr knwn determinants f factr VII, hwever, are diet, bld lipids and genetic factrs 19 " 23. One crss-sectinal study amng rural Finnish men shwed a psitive crrelatin f ttal fat intake and fasting factr VII 24. Results frm interventin studies shw that factr VII increases when the intake f dietary fat increases. This effect is seen in lng-term studies n fasting factr VII as well as in shrt-term studies n pstprandial factr VII level The effect f the fatty acid cmpsitin f the diet used in these interventin studies is nt quite clear. In sme studies a difference in factr VII between diets which differ in fatty acid cmpsitin was fund, while this is nt the case in ther studies 20 ' 25,28,29 ' 32. These studies will be extensively described in Chapter 2. Other dietary factrs which may influence factr VII are dietary fibre and prtein. Factr VII was fund t be inversely related t dietary fibre and psitively t prtein 33 " 36, but clear evidence is missing. In many crss-sectinal studies a psitive assciatin between serum-triglycerides and factr VII has been bserved 16,37 " 43. This relatin is much less apparent in interventin studies n the effect f dietary fat n factr VII in which triglyceride cncentratin is 14

12 General intrductin measured as an intermediating factr' 9,20 ' 25 " 27. The R/Q353 plymrphism in the gene cding fr factr VII is the result f a single base change in the cdn fr amin acid 353 and leads t the replacement f arginine (R) by glutamine (Q) 23. The Q allele is assciated with lwer levels f factr VII. The cmbined effect f diet and genetic factrs was investigated in a very small interventin study amng crnary heart disease patients' 06. It was fund that the respnse f factr VII n a high-fat meal was much higher in patients with the RR gentype cmpared t thse with the RQ gentype. This suggests that the R/Q353 plymrphism may mdify the relatin f factr VII with diet and bld lipids, but there is n extensive evidence fr this hypthesis. Ratinale and utline f this thesis Arterial thrmbsis becmes mre imprtant in elderly peple, since they have a high prevalence f athersclersis. Elevated levels f factr VII, in cmbinatin with the existing athersclersis, may increase their risk f a crnary event. Hwever, n infrmatin n factr VII in elderly is available and it is nt knwn whether in elderly peple factr VII can be altered by diet. Therefre, we studied factr VII in relatin t its majr determinants in elderly peple. A crss-sectinal study and an interventin study were perfrmed t answer the fllwing questins: la. What is the magnitude f the assciatin f factr VII :C and factr VII t with diet and serum-triglycerides in elderly men and wmen? b. D these assciatins vary acrss gentype grups f the R/Q353 plymrphism? 2a. Is, in elderly wmen, the respnse f factr Vila n a fat-rich meal dependent n the fatty acid cmpsitin f the meal? b. D these respnses vary acrss the gentype grups f the R/Q353 plymrphism? This thesis describes the results f a crss-sectinal and an interventin study. T give backgrund infrmatin n the relatin f factr VII with dietary fat, the next chapter describes the state f the art n this tpic at the start f the prject. In Chapter 3 a crsssectinal study n the relatin f factr VII with diet in a large ppulatin f elderly peple is evaluated. The effects f the R/Q353 plymrphism n the assciatin f factr VII with diet and bld lipids in subjects frm the extreme quintiles f the factr VII distributin are described in Chapter 4 and 5. Finally the pstprandial effect f a fat-rich meal n factr VII was investigated in a randmized crss-ver trial in a large grup f 15

13 Chapter 1 elderly wmen. This study is described in Chapters 6 and 7. A general discussin n factr VII, dietary fat and genetic dispsitin can be fund in Chapter 8. 16

14 CHAPTER 2 Cagulatin factr VII, dietary fat and bld lipids: a review L.I. Mermen, E.G. Schuten, D.E. Grbbee, C. Kluft Thrmb Haemst 1996;76:

15 Chapter 2 Intrductin There is cnsiderable, thugh incnclusive evidence, which suggests that cagulatin factr VII is a risk indicatr fr cardivascular disease. In the prspective Nrthwick Park Heart Study (NPHS) high levels f factr VII cagulant activity (FVII:C) were assciated with an increased risk f ischaemic heart disease, which was strnger than the assciatin between high levels f chlesterl and ischaemic heart disease 1. Later this assciatin was fund t be cnfined t fatal events nly 6. Anther prspective study (PROCAM) fund a trend twards higher FVII:C values when nly fatal events were taken int accunt 2. Differences in measurement technique may explain the strnger assciatin in the NPHS cmpared t the PROCAM study. In bth studies a ne-stage cltting assay was used, but with different factr VH-deficient substrate plasma's. When activated factr VII (FVIIa) cncentratins were determined directly, the crrelatin between FVILC and FVIIa was cnsiderably greater fr the NPHS assay than fr the PROCAM assay. If the thrmbtic respnse is determined by the circulating cncentratin f FVIIa, then the NPHS assay seems t be mre specific fr investigating the relatin between factr VII and cardivascular disease 44. A secnd explanatin fr the strnger assciatin in the NPHS might be the practice f the NPHS f btaining bld samples in the nn-fasting state, with the pssibility f increases in FVIIa 28. In the PROCAM study, samples were btained frm fasting individuals. Als, sme crss-sectinal studies were carried ut t investigate the assciatin between factr VII and cardivascular disease. In several studies patients with prir infarctin had significantly elevated levels f FVILC cmpared with patients withut such a histry 45 " 48. The Athersclersis Risk in Cmmunities Study (ARIC) shwed significantly higher FVILC in wmen with cardivascular disease, but nt in men 45. Ttal factr VII (FVIIt) was elevated in first degree relatives f patients with premature ischemic heart disease cmpared t age-matched subjects withut knwn risk factrs 49. Furthermre, patients with crnary artery disease and patients at high risk fr this disease had higher levels f FVIIt cmpared t cntrls 50,51. Finally, patients aged years with thickened cartid arterial wall had a higher FVILC 52, which was nt bserved in yunger patients 53. With a view t preventin f cardivascular disease knwledge f the determinants that influence the knwn risk indicatrs is imprtant. Fr factr VII the mst imprtant determinants seem t be gentype, age, gender, insulin resistance, bdy mass index, dietary fat and bld lipids"' 12 ' 19 ' 20 ' " 59. Of these, dietary fat and bld lipids are subject t change and ptential candidates fr lwering the level f factr VII. T summarize current evidence with respect t dietary influence n factr VII, in this paper recent studies n factr VII, dietary fat and bld lipids will be reviewed. In rder t make the

16 Review article mre cmprehensible, the available methds fr measurement f factr VII will be described first, after which sme attentin will be paid t the mechanisms underlying the relatin between factr VII and dietary fat and bld lipids. A distinctin between acute and chrnic effects f dietary fat is made, as the underlying mechanisms fr these effects may be different. The acute effects are described fr pstprandial factr VII levels (measured in bld samples cllected in the nn-fasting state) and the chrnic effects are described fr the fasting factr VII levels (measured in bld samples cllected in the fasting state). Measurement f factr VII In the circulatin the main prtin f factr VII ccurs in an inactivated frm (factr VII zymgen) and a small prtin in the activated frm. There are several methds fr measurement f factr VII (Figure 2.1). A recent technique is derived frm the ne stage-cltting assay, using a mutant thrmbplastin, which des nt activate factr VII during the measurement. With this technique the activated part f factr VII (FVIIa) can be measured directly 60. FVILC (measured by the ne-stage-cltting assay) reflects the activated part f factr VII in the bld sample and sme factr VII zymgen which is inadvertently activated by this technique. Figure 2.1.Measurement f factr VII 1% 99% activated factr VII unactivated factr VII factr VII in viv \ FVIIa FVHc FVUchr FVUag FACTOR VII ASSAYS 19

17 Chapter 2 Fr this analysis thrmbplastin f several rigins, i.e. rabbit, bvine and human, can be used, resulting in incmparable FVII:C levels 61 ' 62. Only bvine thrmbplastin is hardly capable f activating factr VII zymgen and measurement f FVILC with this thrmbplastin culd be seen as methd t evaluate FVIIa 63 ' 64. Furthermre, the incubatin time f the thrmbplastin with factr VII and the factr VH-deficient plasma, will influence the utcme f the cltting assay Ttal factr VII can be determined by the chrmgenic assay in which all factr VII zymgen is activated and the ttal activity is measured. Anther methd t assess the ttal amunt f factr VII is by immunlgic assay, which des nt discriminate between factr VII zymgen and FVIIa 66. Bth last assays reflect the ttal amunt f factr VII mlecules (factr VII mass) present in the bld sample and shuld give similar results 61. Mechanisms behind the relatin between factr VII and dietary fat Three different mechanisms are suggested by several authrs t explain the relatin between dietary fat and factr VII. Sme f these mechanisms explain nly the relatin with FVIIt, thers nly with FVILC. Binding factr VII Carvalh et al 67 suggest that dietary fat has an effect n factr VII thrugh prlnged halflife time f factr VII in the circulatin, caused by binding f factr VII prtein with triglyceride rich lipprteins (TRLP). In an in vitr study binding f very lw density lipprteins (VLDL), lw density prteins (LDL), high density prteins (HDL) and chylmicrns with FVII was bserved 67. The bnd f FVII with LDL was less strng than with the ther lipprteins. N evidence has been btained fr binding in viv, because n FVIIt was fund in the islated lipprteins. Hwever, the labile adsrptin f FVIIt may have been ablished by the ultracentrifugal prcedure, which was used fr islatin f the lipprteins. These data supprt nly part f the thery; a binding between FVIIt and TRLP in vitr was fund, whether this binding indeed prlngs the half-life time f factr VII prtein has nt been established. Induced synthesis f vitamin K-dependent cltting factrs Anther pssibility fr increased factr VII zymgen might be enhanced synthesis in the liver. It is suggested that activatin f the extrinsic pathway by increased generatin f prthrmbin fragment 1+2 may lead t stimulatin f the hepatic prductin f factr VII and ther vitamin K dependent prteins 27,68. This was shwn in rabbits where intravenus injectin f the fragment 1regin f prthrmbin is assciated with a transient increase in 20

18 Review the plasma cncentratin f factr II and factr X 69. The psitive assciatin f vitamin K- dependent cltting factrs with ttal chlesterl, LDL-chlesterl and triglycerides als supprts this hypthesis 22. In mst studies n the effect f dietary fat n factr VII, hwever, ther vitamin K-dependent cltting factrs have nt been measured, with the exceptin f factr X. The whle set f vitamin K-dependent cltting factrs shuld be cnsidered when this mechanism is further investigated. Activatin factr VII by negatively charged surfaces A third ptin fr the mechanism behind the assciatin f dietary fat with FVILC is activatin f factr XII, and thereby factr VII, by the negatively charged surface f the TRLP 70. Several in vitr experiments shwed that when stearic acid r vesicles, with a negative charge and size similar t TRLP, were added t plasma, FVILC increased in a dse-dependent manner. Oleic acid and ther unsaturated fatty acids had n effect n FVILC 71,72. Lipprtein lipase (LPL) seems t be imprtant in this reactin; when plasma f hypertriglyceridaemic patients with LPL deficiency was treated with LPL factr XII was prmptly activated 73. Thus, lng-chain saturated fatty acids in the interface f lipprtein remnants, prduced by the interactin f TRLP with lipprtein lipase (LPL), appear t prvide the negatively charged surface that activates factr VII. Chrnic effects f dietary fat Several experimental studies have recently been carried ut t examine the effect f fat rich diets n fasting FVILC r FVIIt (Table 2.1). Effects f high-fat and lw-fat diets were cmpared and effects f diets rich in saturated r unsaturated fat n FVILC r FVIIt were examined. Sme studies fcused n the effect f fish r fish-il n FVILC. Effects f high-fat vs lw-fat diets Three randmized crss-ver studies 36,74,75, ne cntrlled 76 and ne uncntrlled 25 interventin study in healthy adults cmpared high-fat with lw-fat diets with respect t FVILC. In all studies, except ne 36, the diets were iscalric and the rati f plyunsaturated and saturated fat was higher in the lw-fat diets cmpared t the high-fat diets. The differences in fat intake between the tw experimental diets ranged in these studies frm 7 en% t 50 en%. In tw studies the change in fat was accmpanied with a change in fibre intake, which must be taken in mind when cmparing the results, since fibre intake might lwer FVILC FVILC was significantly lwer after the lw-fat diet cmpared t the high-fat diet in fur studies 25,36,75 ' 76. Marckmann et al 74 culd nt find an effect f either diet n FVILC, but the difference between the high and 21

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20 Review lw-fat diet was merely 8.3 en%. In the study f Brace et al 25 the effect was even smaller, but the lw-fat diet lasted fr 20 weeks cmpared t 2 weeks in the study f Marckmann et al 74. Hwever, mst f the reductin in FVII:C in the study f Brace et al 25 ccurred during the first fur weeks f the lw-fat perid. The cntradicting results might be due t a difference in rati f the fatty acids f the diets used in bth studies, r by the lack f a cntrl grup in the study f Brace et al 25. One crss-sectinal study in 198 rural Finnish men aged 70 t 89 shwed a psitive crrelatin f ttal fat intake and fasting FVII:C 24. Whether this assciatin indeed reflects chrnic effects f ttal fat intake n FVILC is, hwever, nt clear. There was n difference in FVIIt after a lw r a high-fat diet 2575, but in ne study, where the participants were put n a tw week lw-fat diet after their habitual high- fat diet, FVIIt drpped significantly with 10-15% f initial values 20. Furthermre Miller et al 77 reprted a psitive assciatin between dietary fat intake and FVIIt. Effects f high-saturated vs high-unsaturated fat diets Diets with the same ttal fat cntent, but with a different fatty acid cmpsitin were tested in six randmized crss-ver studies 10 ' 26 ' 27 ' 54,78 ' 79 and ne study in which subjects received dietary cunselling 80. All included healthy subjects between 21 and 66 years and duratin f the diets varied frm three weeks t six mnths. N difference was fund in FVILC r FVIIt between diets cntaining mainly saturated fatty acids (safa), mnunsaturated fatty acids (mufa) r plyunsaturated fatty acids (pufa) 20,54 ' 78 ' 80. Three studies examined the effect f diets differing nly in saturated fatty acid cmpsitin. FVII:^ was significantly lwer after a high stearic acid diet cmpared t a high palmitic r myristic/lauric acid diet 26 ' 27. The decrease in FVILC after a high stearic acid diet was accmpanied by a decrease in FVIIt Slightly higher FVILC levels were fund after a high myristic acid diet cmpared t a high palmitic acid diet 79. Prbably, the stearic acid cntent in saturated fat diets used in the studies mentined abve was nt high enugh t result in lwer FVILC levels after high safa diets. Als, sme substances in the sheabutter (cntaining 7% unsapnifiable material), which was the rigin f the stearic acid, might have influenced the factr VII metablism. One crss-sectinal study shwed a psitive assciatin f FVILC with saturated and mnunsaturated fat. N assciatin was fund between FVILC and plyunsaturated fat 24. This might be due t the lw intake f plyunsaturated fat (mean=14.9 g/day, SD=8.6) in this study ppulatin. Many studies 8 '" 90 payed special attentin t the effect f fish r fish-il supplementatin n fasting FVILC levels, but nly in tw f them 81 ' 90 an effect was bserved. FVILC increased significantly after supplementatin with 10 g fish il daily 81 ' 90. Hwever, in ne 23

21 Chapter 2 f these studies 81 diabetes patients were included in stead f healthy subjects, and in bth studies the fish-il supplementatin was relatively high 81,90. Cncluding remarks Fasting FVILC is likely t decrease after a lw-fat diet cmpared t cnsumptin f a high-fat diet, while the results n fasting FVIIt are nt crrespnding. There is n difference in effect n FVILC r FVIIt after intake f mainly safa, mufa, pufa r fish (il). Apparently the amunt f fat is a mre imprtant determinant f FVILC than the fat cmpsitin. Only stearic acid appears t behave differently with a remarkable lwering effect n FVILC. Acute effects f dietary fat In several studies the effect f dietary fat n pstprandial factr VII levels was examined (Table 2.2). Lw-fat meals were cmpared t high-fat meals and FVILC r FVIIt was measured. Others cmpared the effects f saturated and unsaturated fat meals n FVILC and FVIIt. In patients with hyperlipidaemia r cardivascular disease the effect f ne fatty meal was investigated. The effect f lw-fat vs high-fat The effect f a high-fat meal and a lw-fat meal n pstprandial factr VII levels has been investigated in a number f studies f different designs. A randmized crss-ver study f Marckmann et al 29 the effects f a high-fat (50 %f energy = en%) meal n FVILC and FVIIt in six healthy males (21-30 years) was investigated. The meal resulted in a high pstprandial FVILC peak. FVIIt varied insignificantly during the 24-h perid. A secnd study with similar design shwed als an elevatin f FVILC after a high-fat meal, but pstprandial FVIIt was lwer cmpared t fasting levels 30. Silveira et al 31 and Mr et al 91 cnducted a fat-tlerance test amng 33 patients wh survived a first mycardial infarctin and 10 healthy cntrl subjects (mean age 48.8 ± 3.2 years). Levels f FVILC increased in bth grups, but mre prnunced in cntrl subjects. In cntrast, FVIIt tended t be lwer in the three-hur sample in patients and cntrls and gradually returned t baseline twards the end f the 12-hur perid. In tw randmized crss-ver studies FVILC increased after tw high-fat meals 32,92 cmpared t a fat-free meal. The difference between ne f the high-fat meals and the fat-free meal after eight hurs was 10.4% 32. This difference is large enugh t have bilgical significance, since the difference in FVILC between peple with n ischaemic heart 24

22 Review disease and thse with (fatal) ischaemic heart disease is 4-10%' 2,93. FVIIt decreased after all meals in ne study 32, while it increased nly after a high saturated fat meal and did nt change after the fat free meal in anther study 92. The effect f a lw-fat meal (20 en%) was evaluated in tw studies with similar design 29,30. In ne study FVII:C increased after the lw-fat meal, but nt as much as after a high-fat meal. Factr Vllt did nt change. The ther study shwed a decrease in FVII:C and FVIIt after the lw-fat meal. The effect f high saturated vs high unsaturated fat The respnse f FVII:C and FVIIt n a meal with mainly saturated r unsaturated fat was cmpared in different crss-ver studies amng small numbers f healthy middle-aged subjects 2832 ' 92. Tw studies included a lw-fat cntrl meal 32,92. In the study f Salmaa et al 32 the pst-prandial effect f a fat meal was tested, while the ther studies evaluated the pst-prandial effects after a ne r fur-week diet 28 ' 92. There was n difference in the pstprandial change f FVILC r FVIIt between the high saturated and high unsaturated meal in tw studies Hwever, in ne study FVILC was highest n the saturated fat meal, intermediate n the unsaturated fat meal and lwest n the cntrl meal. Factr Vllt levels did nt differ significantly between the unsaturated fat and cntrl meal, but were significantly increased n the saturated fat meal 92. Cncluding remarks Sme f the studies mentined abve cmprised a diet-perid f several days where bld samples were taken n the last day f each diet-perid. In thers the effect was just evaluated after ne test-meal. Als, the cmpsitin f the meals, the number f participants and the time f bld sampling differed between the studies. Nevertheless, results were in general quite similar. Furthermre, in studies n acute effects as well as in studies n chrnic effects f dietary fat n factr VII mre r less the same cnclusins can be drawn; an increase after a high-fat meal/diet and prbably n different effects f several fatty acids. There seems t be n difference in pstprandial respnse f FVILC r FVIIt between saturated fat cnsumptin and unsaturated fat cnsumptin, but this might be due t lw numbers. FVIIt des nt appear t increase after any type f meal. Prbably factr VII prtein nly decreases due t endgenus fluctuatins. FVILC always 25

23 E u a > b. Z ffi td Q U w CO (Z> b OS 0. t" H -1 w S» > 4J > </3 <S> O a u N S T3 C cd h* r- CN +1 c c CN g n c cd CO 4 d Tt 00 Cd e 03 CO E (A u cd >> -C «CN c c c <4-l 1 < <L> > t/1 IM T3 u N s c cd co CN ON S CO " c CN CO V5 JH >. -C cd \ ON CN c CN $ * > -> > u > IA O fc T3 <U N s T3 C ed CN 00 (N 4 ON ^ ^H s 00 -* c c 60 cd >> B 73 u j = ^ u 3 'a. JH "A 6 <22 (A JD 15 r- c 1 u > VI V) s- - GO N "E T3 c ed u> u 73 6 ia e» IN OS. «- < u > ta <s> O T3 U N 1 a c «L- c-j <N CT\ S m c-» 3" IA JO 73 E >» -C ^ ON (N c N - -,«M -C W) 3 ^ «<D > <A Urn T3 <U N 6 T3 C ed u CS 00 CN 4 O^ ' MM S CQ Tir O <u 60 «>. f "«<u x: ^^ t/3 3 & U3 "«E i«<v E r- m» < B c ed _u ",<& <4-> Tf <u 00 «c E c 1 c rt 'a S E i/i tc cd X) t> > 3 J= S c CO cd a, CO ON + CO ^q CO +1 CN Ov ^ p cd c cd CO E LO CO ^ 3 n a CJ J3 cd CO "O c CN CO +t -> <r~ u CO > O n (A O <- a u M 'E O c cd t_ f- (N +t CO CO CN S CD c cd CO E ^ ' d +1,^cd c cd u E c/> ^a> 75 E >. JC cd CO O CN CO cd J= p 3 < < «- Ui CO > t/1 VI O u- u - CO N 's c ed u 73 E i/t Jt! *c3 E ^> CN ON I <- 1- <u > IA Ui TD CO N s T3 a cd u. >> ^ 73 CO JZ ia CO 73 E *S Tt W5 u 73 E in CN > <- t- <U > IA IA O IM CJ T3 CO N E T3 C cd t- t~- CN +1 CO CO CN s QQ c cd CO E Tt d +1 Tf CO 00 cd c ed CO e IA JD 73 E >* sz cd CO O CN CO cd < cd c 3 -C 3. < la CO > (/) («l-h u T3 (U M "B T3 C ed u- c cd E «S «U 73 TJ- CN ON 1 <rb CO > O V) vi O i- y T3 CO N 'E T3 C cd i- 73 CO J= IA CO 73 E t «jy E in CN

24 Review respnds with an increase after high-fat meals, but it is nt yet clear whether this respnse als ccurs after a lw-fat meal. Bld lipids Bld lipids may have an imprtant rle in the relatin between dietary fat and factr VII. Many researchers have investigated this by relating bld lipids t (fasting r pstprandial) factr VII in bld samples taken at the same time. In these studies triglycerides and FVILC r FVIIt were analyzed. Als, ttal chlesterl, HDL chlesterl r smetimes LDL chlesterl were measured. Furthermre, the assciatin f triglycerides and chlesterl with factr VII was evaluated in interventin studies n chrnic effects f a diet n factr VII. Since the design f these interventin studies is described abve, we will nt g int detail n this here. Finally the relatin between bld lipids and FVILC and FVIIt was investigated in patients with primary hyperlipidaemia. Factr VII and triglycerides All crss-sectinal studies which included measurements f triglycerides shwed a psitive crrelatin between triglycerides and FVILC ' 9497, r FVIIt Fur f the studies did nt cmprise wmen 2438,39-95 and ne study, in which FVILC and FVIIt measurements were dne amng men and wmen, shwed nly a crrelatin between triglycerides and FVIIt in men 4 '. The participants in this study were relatively yung (mean age men 23 and wmen 24 years) cmpared t ther studies which were carried ut amng middle-aged r elderly peple, s the studies might nt be cmpletely cmparable. In mst f the studies factr VII was measured after an vernight fast, the authrs f tw articles, hwever, did nt mentin the state f the participants when bld samples were drawn In eight interventin studies triglycerides and FVILC were measured. Nne f these studies shwed a psitive assciatin between triglycerides and FVILC " In five studies FVILC decreased after a lw-fat diet, while triglycerides did nt change r even increased 2574 " 76. Factr VII and chlesterl Findings n the relatin f serum chlesterl cncentratin with factr VII in healthy subjects are much less cnsistent. Eight ut f 13crss-sectinal studies shwed a psitive assciatin between ttal chlesterl and FVILC , r FVIIt 37-4 ' which was strnger in men than in wmen 3741,98. HDL and LDL chlesterl psitively crrelated with FVILC in ne study 94 while they 27

25 Chapter 2 were psitively assciated with FVIIt nly in men in anther study 41. In several studies a crrelatin between thse parameters culd nt be fund at all 16,37-38,40,41,94,97. Finally, Yang et al" reprted a psitive crrelatin between ttal chlesterl/hdl chlesterl rati and FVIIt in 48 healthy men. In tw interventin studies a psitive assciatin between ttal chlesterl and FVILC was fund 20 ' 36. In six ther studies the change in ttal chlesterl was cherent with the change in factr VII, but nthing was mentined n the assciatin between these variables 25,27,74 " Factr VII in hyperlipidaemic patients Patients with primary hyperlipidaemia, type Ha, lib r IV f the Fredricksn classificatin' 00 participated in several studies in which fasting factr VII and bld lipids were measured 55 ' 01 ' 02. FVILC and FVIIt were higher in middle-aged patients with type Ha, lib r IV hyperlipidaemia cmpared t healthy cntrls f the same age 55,10 ' 102. Fr FVIIt this difference was nt significant 55,10 '. Anther study amng elderly patients, shwed elevated FVILC and FVIIt levels in patients with type Ha and lib but nt in type IV hyperlipidaemia cmpared t cntrls 103. Nrdy et al 104 fund ppsite results in a study where patients with type IV but nt type Ha and lib had higher FVIIt levels. One explanatin fr these cntradictry results might be that in the latter study a different methd was used t measure factr VII (factr VII nrmtest, which measures FVIIphsphlipid cmplex) and that bld samples were nt taken after an vernight fast 104. Other differences between studies might further have cmplicated the results; sme patients received treatment, but accrding t the authrs this treatment did nt interfere with cagulatin parameters. Sme cntrls used lipid-lwering diets, but this des nt explain the different results fund fr type II and IV hyperlipidaemic patients. In view f the evident relatin between triglycerides and factr VII and the weak assciatin between chlesterl and factr VII, it culd have been expected that factr VII was higher in patients with increased levels f triglycerides, i.e. type lib and IV hyperlipidaemia. Still, this was nt cnfirmed in the studies mentined abve. Cncluding remarks There is cnvincing data frm crss-sectinal studies which shw a relatin between triglycerides and FVILC r FVIIt. This is nt cnfirmed by results frm interventin studies. The crss-sectinal assciatin might nly reflect the assciatin f FVILC and triglyceride after a fat-rich (evening) meal. This indicates that the change in factr VII after a lng-term diet is independent f triglycerides, while pst-prandial change in factr VII des depend n triglycerides. 28

26 Review The assciatin between different subfractins f chlesterl and FVII:C r FVIIt is nt quite clear. This may be due t different types f participants in studies perfrmed thus far; diabetes patients, hypertensive patients, r healthy participants were included. Als, differences in age distributin f the participants may have accunted fr the discrepancy in results. Mre likely hwever, the relatin f chlesterl with FVILC and FVIIt is due t the assciatins between FVILC and large lipprtein particles, chylmicrns, VLDL and IDL 70. The interrelatin between triglycerides and chlesterl might explain the assciatin f factr VII with chlesterl. Unfrtunately in the reprted studies, the assciatins between chlesterl and factr VII were nt adjusted fr triglyceride levels. Gene-envirnment interactin: factr VII plymrphism and triglycerides FVII plymrphism Recently a plymrphism fr the factr VII gene was identified, which is strngly assciated with plasma FVILC levels 23. The base change causing the plymrphism is a G t A substitutin in the secnd psitin f the cdn fr amin acid 353, leading t replacement f arginine (R) by glutamine (Q) in the prtein prduct f the allele (R/Q353). The Q allele is assciated with relatively lw FVILC levels while, the R allele is assciated with relatively high FVILC levels 23,57 ' 05 ' 07. In Caucasians Q allele frequencies f 0.06, 0.09, 0.10 and 0.13 have been reprted 23 ' In Dravidian Indians, Gujaratis and Afr-Caribbeans the frequency f this allele was 0.29, 0.25 and 0.08 respectively Interactin with dietary fat and triglycerides Lane et al 57 reprted that the assciatin between triglycerides and FVILC amng Caucasians, Afr-Caribbeans and Gujarati Indians depended n the R/Q353 gentype. In the Gujaratis n crrelatin between triglycerides and FVILC was fund amng thse with the Q allele, while a crrelatin was present in persns with the RR gentype. The same results were fund in a study by Humphries et al 58, wh examined FVILC and FVIIt in 364 Caucasian men. Hwever, in a study f Saha et al 105, where fasting FVILC levels were cmpared with triglyceride levels in Dravidian Indians, the ppsite was true; the relatin between triglycerides and FVILC was strnger in persns with the RQ r QQ gentype than in persns with the RR gentype 105. In a study f Silveira et al male pst-infarct patients underwent a fat-tlerance test and FVIIa, FVIIt and triglycerides were measured. The assciatin between pstprandial triglycerides respnse and fasting FVIIt was nt significant in participants with the RQ gentype, while it was significant in thse with the RR gentype. In bth the RQ grup and the RR grup a significant assciatin between triglyceride and FVIIa respnse n the test meal was fund. It is likely that the 29

27 Chapter 2 plymrphism cnsiderably mdifies the assciatin between fasting factr VII levels and triglycerides. It is, hwever, frm these studies nt clear whether this assciatin is strnger in persns wh carry the Q allele r in thse with the RR gentype. This might be due t the fact that the R/Q353 plymrphism itself is nt a direct determinant f the factr VII respnse, but may be in strng allelic assciatin with sme causative plymrphic sequence smewhere else n the factr VII gene. There are s far little data which suggest that the gentype influences the pstprandial respnse f FVIIa n a fat lad. In the study f Silveira et al 106 FVIIa increased in bth gentype grups in respnse t fat intake and the differences between RR and RQ individuals in the fasting state were maintained in the pstprandial state 106. The abslute pstprandial rise in FVIIa was higher in the RR grup than in the RQ grup. Hwever, s far this study is the nly pstprandial study in which gentype has been taken int accunt. Cnsidering this, and the cntradicting results f studies n the effect f gentype n the assciatin between triglycerides and factr VII, mre research is needed t dcument the interrelatins between factr VII, triglycerides, dietary fat, R/Q353 and ther plymrphisms. Discussin and cnclusin It is nt surprising that results f studies investigating factr VII are nt always cnsistent. Several methds are presently used t measure factr VII, nt all f which are cmparable. The methd mst widely used, i.e. ne-stage cltting assay, is the ne with mst uncertainty n what is actually measured. As the activated frm f factr VII has a priming functin in triggering the cltting cascade, measurement f FVIIa seems the mst relevant way t study factr VII. S far this methd has rarely been used in studies n factr VII and dietary fat. Anther cmplicatin is the difference in timing f bld sampling; results f studies n fasting and pstprandial levels are in fact incmparable. Mre imprtantly, different mechanisms might accunt fr effects f dietary fat and bld lipids n fasting and pstprandial factr VII. Fr example, after a lng-term high-fat diet, fasting levels might be higher, but als the respnse f factr VII n a fat lad might be mre prnunced than after a lng-term lw-fat diet. It is knwn, fr example, that the respnse f lipprteins n a fat lad is nt nly dependent n the type f fat given but als n the type f fat which is habitually cnsumed 108. Furthermre, the R/Q353 plymrphism prbably mdifies this reactin. Factr VII is a risk indicatr fr cardivascular disease, the assciatin being strnger between factr VII and fatal events than nn-fatal events. Trace amunts f FVIIa 30

28 Review represent the very first active prtease in the extrinsic pathway f cagulatin and elevated plasma levels f FVIIa may give rise t an extensive initiatin f the cltting cascade after rupture f athersclertic plaques. Factr Vila may in particular be imprtant in the utcme f a thrmbtic event, perhaps thrugh the eventual size f the cclusive thrmbus. Fr the purpse f preventin f cardivascular disease thrugh a change in dietary habits, it is necessary t knw if and hw the level f FVIIa can be influenced. In this cntext, it is gd t reflect n the mechanism that might explain the relatin between dietary fat and factr VII. Data f studies n this tpic are insufficient t thrw light n which f the mechanisms that are prpsed is really relevant. There are still many questins t be slved. Fr example, why d we nt find an increase in FVII:C after saturated fat intake and a decrease after cnsumptin f fish(il), since the half life time f chylmicrn remnants is lnger after a saturated fat meal and shrter after intake f fish il Furthermre, in the fasting state almst n large lipprtein particles are present in the circulatin; n activatin by lipprteins can ccur, s hw des that explain the higher fasting FVII:C levels fund after a high-fat diet in sme studies? Answers t these questins culd supprt r refine the presently prpsed mechanisms r reveal a new thery. Many studies have been perfrmed suggesting that factr VII, dietary fat and bld lipids are smehw related, independent frm ther factrs. It seems quite clear that the amunt f fat intake is imprtant; high-fat meals increase factr VII. Whether fat cmpsitin is f any imprtance remains t be clarified. Interventin and bichemical studies are needed t investigate this and t find the explaining mechanism behind this relatin. Fr further research it is advisable that ttal factr VII and FVIIa is measured with ne standard technique fr each methd, and that bld is cllected at fasting and pstprandial cnditins. Als, the plymrphisms f the gene cding fr factr VII shuld be taken int accunt while studying the relatin between factr VII, dietary fat and bld lipids. 31

29 CHAPTER 3 The assciatin f dietary fat and fibre with cagulatin factr VII in the elderly: The Rtterdam Study Abstract Cnsiderable evidence suggests that a high cncentratin f cagulatin factr VII is a risk indicatr fr ischaemic heart disease. Factr VII is knwn t be influenced by dietary fat and prbably by dietary fibre in yung and middle-aged peple. There are n data available in elderly peple and the effects f different types f fat are unclear. This study examines the relatin f factr VII cagulant activity (FVII:C) with dietary fat and fibre in The Rtterdam Study. The Rtterdam Study is a ppulatin-based study amng 7983 men and wmen, aged 55 years and ver. FVILC was measured in 3007 subjects (1730 wmen and 1277 men, mean age 67.3 ± 7.8 and 66.3 ± 7.0 years respectively). Measurements included cardivascular risk factrs and habitual diet was assessed by a semiquantitative fd-frequency questinnaire. Assciatins that were statistically significant r nearly significant differed fr sme nutrients between men and wmen. Ttal fat intake shwed a direct assciatin with FVILC nly in wmen (6=0.1 %/g, 95%CI:0.01,0.20). Saturated fat intake was assciated with FVILC in wmen (6=0.18 %/g, 95%CI: ,0.36) and in men (6=0.11 %/g, 95%CI:-0.06,0.27). Mnunsaturated fat was psitively related t FVILC in wmen (6=0.17 %/g, 95%CI:-0.05,0.39 and plyunsaturated fat was inversely assciated with FVILC in men (6=-0.15 %/g, 95%CL-0.33,0.03). Fibre intake was inversely assciated with FVILC in bth men (6=-0.31 %/g, 95%CL-0.57,-0.06) and wmen (6=-0.36 %/g, 95%CL-0.63,-0.09). N assciatins were fund fr energy intake. In elderly peple FVILC is assciated with fat and fibre intake. This suggests that FVILC is influenced by nutritinal factrs, even at ld age. L.I. Mennen. J.C.M. Witteman, J.H. den Breeijen, E.G. Schuten, P.T.V.M. de Jng, A. Hfman, D.E. Grbbee Am J Clin Nutr 1997;65:

30 Chapter 3 Intrductin Factr VII is ne f the cagulatin factrs f the extrinsic pathway f the cagulatin cascade. This pathway is activated during vascular injury, which results in the rapid frmatin f a bld clt. A high cncentratin f factr VII cntributes t a high thrmbtic tendency. In the presence f athersclersis, this tendency may be a trigger fr a cardivascular event. Athersclersis is cmmn in elderly peple, reflecting a develpment ver many years. The effects f thrmbsis, hwever, are acute and subject t change even at lder ages. Increased thrmbtic tendency in elderly peple cnstitutes an elevated risk fr cardivascular disease and cnsiderable evidence indeed suggests that factr VII cagulant activity (FVILC) is a majr cntributr 1,2. In the Nrthwick Park Heart Study (n=1511) factr VII was fund t be a risk indicatr fr ischaemic heart disease' and in the PROCAM study (n=10581) this seemed t be the case when nly fatal events were taken int accunt 2. Tw nutritinal factrs, dietary fat and fibre, are cnsidered majr envirnmental determinants f FVII:C. Frm several interventin studies amng yung adults it is knwn that FVILC depends n dietary fat intake' 030 " 3236,92. A high-fat diet results in high FVII:C levels and after a fatty meal pst-prandial FVILC rises cncmitantly with the rise in triglycerides 30 " 32,92. These changes in FVILC are believed t be independent f the type f fat cnsumed 20,36. The results frm three bservatinal studies amng middle-aged men hwever, are incnsistent 34,36 " 0. Cnnely et al" and Miller et al 36 bserved an assciatin between FVILC and dietary fat whereas Rankinen et al 34 did nt. Three crss-ver trials in yung and middle-aged subjects shwed a decrease in FVILC after a high-fibre diet 35,75,76. An assciatin between dietary fibre and FVILC was als bserved in ne crss-sectinal study 34. N ther nutrients have cnsistently been fund t be assciated with FVILC 30,36. T ur knwledge, there are n published data n FVILC and dietary factrs in elderly peple. It is imprtant t knw whether the assciatin f FVILC with dietary factrs als exists at an age when mst cardivascular events ccur. Because the level f FVILC directly influences the thrmbtic tendency, in the presence f athersclersis it may determine whether a cardivascular event is triggered. We studied the relatin between FVILC and dietary fat and fibre in the Rtterdam Study. 34