Diet and Peripheral Arterial Occlusive Disease: The Role of Poly-, Mono-, and Saturated Fatty Acids

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1 Americn Journl of Epidemiology Copyright 1991 by The Johns Hopks University School of Hygiene nd Public Helth All rights reserved Vol. 133, No. 1 Prted U.S.A. Diet nd Peripherl Arteril Occlusive Disese: The Role of Poly-, Mono-, nd Sturted Ftty Acids Kle Ktsouynni, 1 Ynnis Sklkidis, 1 Eleni Petridou, 1 Antoni Polychronopoulou- Trichopoulou, 2 Wlter Willett, 3 nd Dimitrios Trichopoulos 3 A cse-control study concerng the ssocition between diet nd peripherl rteril occlusive disese ws conducted Athens, Greece. The cse series consisted of 100 ptients with this disese, wheres controls were 100 ptients with conditions requirg mor surgicl cre who were dmitted to the sme techg hospitl. Diet ws scerted through semiquntittive food frequency questionnire. Nutrient tkes for dividuls were estimted by multiplyg the nutrient content of selected typicl portion size for ech specified food item by the frequency tht the food ws used per month nd summg these estimtes for ll food items. Dt were nlyzed usg multiple logistic regression procedures, controllg for totl energy tke by tkg nutrient residuls nd by usg multivrite nutrient density models. Sturted ftty cids (odds rtio (OR) nd 95% confidence tervl (Cl) contrstg the 75th centile (upper) with the 25th centile = 1.96 nd ), protes (OR = 2.86, 95% Cl ), nd dietry cholesterol (OR = 6.07, 95% Cl ) were ssocited with cresed risk of peripherl rteril occlusive disese, wheres polyunsturted ftty cids (OR = 0.48, 95% Cl ) nd crude fiber (OR = 0.33, 95% Cl ) were relted to reduced risk. Monounsturted ftty cids nd, by ference, olive oil occupy n termedite neutrl position between polyunsturtes nd sturtes (correspondg OR = 1.14, 95% Cl ). Higher tkes of fiber nd vitm C were ssocited with lower risk of peripherl rteril occlusive disese. The low occurrence of therosclerotic diseses Greece nd other Mediterrnen countries my be due to the substitution of olive oil plce of sturted fts nd/or the consumption of diet high vegetbles, fruits, nd other fiber-contg foods. Am J Epidemiol 1991;133:24-. rteril occlusive diseses; rteriosclerosis; cholesterol; diet; ftty cids Atherosclerosis is diffuse nosologic entity (1). Ptients with coronry hert disese re five times more likely to develop overt peripherl rteril occlusive disese nd, Received for publiction October 23, 1989, nd fl form June 12, Deprtment of Hygiene nd Epidemiology, University of Athens Medicl School, Athens, Greece. 2 Deprtment of Nutrition nd Biochemistry, Athens School of Public Helth, Athens, Greece. 3 Deprtment of Epidemiology, Hrvrd School of Public Helth, Boston, MA. Reprt requests to Dr. Dimitrios Trichopoulos, Deprtment of Epidemiology, Hrvrd School of Public Helth, 677 Huntgton Avenue, Boston, MA This study ws prtly supported by grnt from the Commission of the Europen Communities. conversely, ptients with peripherl rteril occlusive disese re four times more likely to develop coronry hert disese (2-4). There is overwhelmg evidence tht serum cholesterol nd, prticulr, low density lipoprote cholesterol nd very low density lipoprote cholesterol re importnt risk fctors for coronry hert disese (5), nd there is vst mount of literture concerng the reltion between diet nd serum lipids (6). By contrst, there re few studies concerng the reltion between diet nd coronry hert disese (7-10), nd the results rem conclusive (11-13). Furthermore, we re not wre of studies concerng the ssocition between dietry pt- 24

2 Diet nd Peripherl Arteril Disese 25 terns nd peripherl rteril occlusive disese, even though therogenesis my be more evident peripherl thn coronry rteries (4). We report the results of study concerng the ssocition between diet nd peripherl rteril occlusive disese Greece. Prticulr emphsis ws given to the possible role of olive oil s dietry fctor tht my limit the occurrence of therosclerosis. Olive oil is n importnt component of the Mediterrnen diet, nd Mediterrnen countries re known to hve low coronry hert disese cidence nd mortlity (14, 15). MATERIALS AND METHODS This pper focuses on the nlysis of nutritionl dt provided by series of 100 ptients with peripherl rteril' occlusive disese nd 100 hospitl controls. Dt concerng nonnutritionl risk fctors nd descriptive prmeters hve been published (16). Briefly, cses were ptients with prcipl dignosis of peripherl rteril occlusive disese consecutively dmitted, over n 18-month period, to mjor techg hospitl Athens. This is one of five generl techg hospitls Athens nd one of 20 mjor hospitls the Greter Athens Are. The hospitl is situted the northern prt of the city, but the ctchment re is not esily defble, sce the referrl ptterns re hevily fluenced by decisions of dmistrtors of severl helth funds, s well s by physicins' choices nd ptients' preferences. Peripherl rteril occlusive disese ptients hd to hve specified bnorml fdgs the Doppler ultrsound flowmeter exmtion nd the ortic or femorl rteriogrphy; controls were ptients rndomly chosen mong those hospitlized the sme hospitl durg the sme period s the dex cses for 14 different conditions requirg mor surgicl cre. Among these conditions the most common were hernis (25 ptients), frcture or trumtic juries (17 ptients), ctrct (14 ptients), ppendicitis (8 ptients), nd vricose ves (7 ptients), followed by simple goiter (5 ptients), externl bscesses (4 ptients), other sk conditions (5 ptients), vrious er, nose, nd throt conditions (7 ptients), nd others (8 ptients). nd controls were not mtched for ge but were frequency mtched for sex. were excluded if they hd clicl history, clicl symptoms, or clicl signs of peripherl rteril occlusive disese. All terviews were conducted by one of the uthors (Y. S.). The terview ws lwys conducted directly with the ptient before the first dmission dischrge. In the terview, dt concerng demogrphic, socioeconomic, nd medicl vribles were recorded nd dietry histories were obted. All ptients were sked to dicte the verge frequency of consumption, over period of 1 yer before the onset of the present disese, of 110 food items or beverge ctegories ccordg to precoded levels of tke per month, per week, or per dy. The frequency of consumption of different food items ws eventully quntified pproximtely terms of the number of times per month the food ws consumed, s done by Grhm et l. (17), Dles et l. (18), nd Trichopoulos et l. (19). Thus, vlue of ws ssigned to food items consumed lmost every dy; vlue of 4 to those consumed bout once week; vlue of 2 to those consumed t lest once month but not every week; nd vlue of 0 ws ssigned to food items rrely or never consumed. Nutrient tkes for dividuls were estimted by multiplyg the nutrient contents of selected typicl portion for ech specified food item by the frequency tht the food ws eten per month nd ddg these estimtes for ll food items. Food composition dt were bsed primrily on vlues obted from the University of Msschusetts nutrient dtbse. Vlues for specil Greek foods were computed from typicl recipes (20). Specificlly, the followg nutrient tkes were estimted: prote (g), totl ft (g), sturted ft (g), monounsturted ft (g), polyunsturted ft (g), cholesterol (mg), crbohydrtes (g), sucrose (g), crude fiber (g), vitm C (mg), nd totl energy tke (kcl). In order to vestigte the ssocition of the estimted nutrient tkes to peripherl

3 26 Ktsouynni et l. rteril occlusive disese, prelimry nlysis ws undertken bsed on the comprison of the frequency distributions of cses nd controls by levels of dividul nutrients. Three levels were used, tkg s cutoff pots the tertiles of the distribution of ll subjects (cses nd controls combed) for every dividul nutrient. Sce, however, most nutrients re positively correlted with totl energy, two pproches were used to control for the potentil confoundg effect of energy tke. First, clorie-djusted nutrient tkes were computed usg simple ler regression models with specific nutrient s the dependent vrible nd cloric tke s the dependent vrible. Residuls were then clculted (21). These clorie-djusted nutrient tkes were then lterntively or simultneously used s dependent vribles, together with totl energy tke, multiple logistic regression models. This procedure ws used to evlute the nutrient-disese ssocition, controllg for totl energy tke. Odds rtios were estimted from the logistic models. Second, the density of specific mcronutrient, expressed s the percentge of totl energy tke, s well s totl energy tke, ws used the sme regression model. This model, referred to s the "multivrite nutrient density model" (22), llows ssessment of the effect of dietry composition (such s the helth effect of 40 percent clories from ft vs. percent) nd is directly terpretble for dietry recommendtions. In ll multivrite nlyses, core model ws used order to control for ge, sex, yers of schoolg, smokg hbits, regulr lcohol nd coffee tke, nd Quetelet dex (weight (kg)/height (m) 2 ), sce these vribles re relted to the risk of peripherl rteril occlusive disese nd my lso be dependently relted to dietry ptterns. By contrst, some fctors tht re risk dictors for peripherl rteril occlusive disese (e.g., hypertension, dibetes, nd, theoreticlly, hypercholesterolemi) were not djusted for the nlysis, sce they my be considered s representg termedite steps the cusl lk, if ny, between diet nd peripherl rteril occlusive disese (23). RESULTS Tble 1 shows univrite chrcteristics of 100 ptients with peripherl rteril occlusive disese nd 100 comprison ptients. There re cler differences some of these vribles tht were ll cluded the core model ll subsequent nlyses (unless otherwise dicted). Univrite frequency distributions of cses nd controls by mrgl tertiles of ll the studied nutrients, s well s the men ± stndrd devition of ll nutrient mesurements for cses nd controls, re described tble 2. Given the tercorreltions between the vrious nutrients, these dt re not directly terpretble. Nevertheless, it is evident tht totl energy tke is not mjor risk fctor, tht polyunsturted ft nd sturted ft hve probbly opposite effects, tht crude fiber nd vitm C my be negtively relted to the risk of peripherl rteril occlusive disese, nd tht prote nd cholesterol tke re probbly strong risk fctors for this disese. Odds rtios of peripherl rteril occlusive disese contrstg the 75th centile with the 25th centile of the distribution of specific nutrient residuls, controllg for totl cloric tke nd other vribles the core model, re displyed tble 3. For given mount of totl energy tke, sturted ft hs detrimentl effect nd polyunsturted ft hs protective effect, wheres monounsturted ft ppers neutrl with respect to the risk of peripherl rteril occlusive disese. Although the dt tble 2 for polyunsturted ft suggested the possibility of nonler reltion, qudrtic term (polyunsturted ft to the second power) ws fr from significnt (p = 0.39), dictg tht the pprent nonlerity ws esily comptible with chnce. Totl crbohydrte tke ppers protective, probbly becuse of its substitution for sturted ft nd possibly becuse of the protective effect of crude fiber. Prote tke nd cholesterol tke re strong risk fctors for peripherl rteril occlusive disese possibly, to cert extent, becuse of confoundg due to sturted ft. The vribles dicted tble 3 were troduced

4 Diet nd Peripherl Arteril Disese 27 8 I< I I u s 0) (A (0 o "5 1 co I»c 1 5 O 3 m 8 I I u. Ai I en (o w to >» 8 e o> 2? Peripherl rteril occlusive co o> co CM co CM,_ 74 ± ± 0.04 '71 ±0.' S ci +1 CM co co r- co CM «* o> 1- $2 CD disese D 5 lterntively the core model, which lso cluded totl energy tke; when sturted ft nd cholesterol were simultneously troduced this model, their regression coefficients were slightly reduced but remed significntly different from the null vlue. The ddition of terms for dibetes (entered s 0, 1 vrible, nd seprte vrible for fstg blood sugr mong dibetics) did not pprecibly lter the coefficients for sturted, monounsturted, nd polyunsturted fts. Vitm C nd crude fiber were lso versely relted to the risk of peripherl rteril occlusive disese. When these two nutrients were simultneously troduced model cludg both sturted nd polyunsturted ft s well s the core vribles, their regression coefficients becme slightly closer to the null vlue but remed significntly different from it. Tble 4 shows odds rtios for peripherl rteril occlusive disese ssocited with n crese of 1 percent the energy density of sturted, monounsturted, nd polyunsturted fts (expressed s the percentge of totl energy), djusted for totl energy tke nd the core model fctors. The results re qulittively similr to those obted when the residuls method ws pplied (tble 3). They dicte, g, tht sturted ft hs detrimentl effect for peripherl rteril occlusive disese nd tht polyunsturted ft hs protective effect, wheres monounsturted ft ppers neutrl with respect to the risk of this disese. Interction terms between ny prticulr nutrient density nd the correspondg nutrient were fr from significnt (p = 0.34 for sturted ft, 0.22 for monounsturted ft, nd 0.75 for polyunsturted ft), wheres terction terms between ny prticulr nutrient density nd energy tke re the correspondg nutrients themselves. Tble 5 shows multiple logistic regressionderived odds rtios for peripherl rteril occlusive disese ssocited with 100-kcl crese of the mjor energy-genertg nutrients. These estimted odds rtios re djusted both mutully nd for the core vribles previously dicted (nd lso shown the footnote of tble 3). It should be noted

5 28 Ktsouynni et l. TABLE 2. Frequency distributions by mrgl tertiles nd men vlues of dily consumptions of ll the nutrients studied, for 99 cses of peripherl rteril occlusive disese nd 98 comprison ptients*: Athens, Greece, 1988 Energy Totl ft Vrible Sturted ft Monounsturted ft Polyunsturted ft Totl crbohydrtes Sucrose Crude fiber Prote Cholesterol Vitm C Subjects 1 (low) * There re missg vlues for one cse nd two controls, t x 'or ler trend nd correspondg two-tiled p vlue. TABLE 3. Odds rtios (OR) of peripherl rteril occlusive disese, djusted for energy nd vrious nonnutrient risk fctors,* contrstg the 75th with the 25th centile of the distribution of specific nutrient residuls: Athens, Greece, 1988 Vrible Totl ft Sturted ft Monounsturted ft Polyunsturted ft Totl crbohydrtes Sucrose Crude fiber Prote Cholesterol Vitm C OR (75th vs. 25th centile) 1.23 ( )t 1.96( ) 1.14( ) 0.48 ( ) 0.44 ( ) 1.04( ) 0.33( ) 2.86( ) 6.07( ) 0.34( ) * Sex, ge (four 10-yer group ctegories), yers of schoolg (contuous), smokg hbits (four ctegories: nonsmokers, pst smokers, current smokers of up to 1 pck per dy, current smokers of more thn 1 pck per dy), lcohol tke (three ctegories: nondrkers, drkers of up to ne glsses per week, drkers of 10 or more glsses per week), coffee drkg (non- nd occsionl drkers, regulr drkers), nd Quetelet's dex (contuous). t Numbers prentheses, 95% confidence tervl. Tertiles (high) xt (p vlue) 1.042(0.) 1.106(0.27) 1.643(0.10) 1.736(0.08) (0.34) (0.48) (0.93) (0.05) (<10" 3 ) 5.6 KIO- 6 ) (0.007) Men ± stndrd devition 2,100.9 ± ,019.1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 42.7 TABLE 4. Odds rtios (OR) nd 95% confidence tervls (Cl) of peripherl rteril occlusive disese ssocited with n crese of 1% the energy density of sturted, monounsturted, nd polyunsturted fts (expressed s percentge of totl energy)*: Athens, Greece, 1988 Vrible OR 95% Cl Sturted ft Monounsturted ft Polyunsturted ft Adjusted for energy tke nd for the vribles sex, ge, yers of schoolg, smokg hbits, lcohol tke, coffee drkg, nd Quetelet's dex. tht this model totl energy is not troduced s n dependent vrible to void overprmeteriztion; ny cse, totl energy is not significnt or importnt risk fctor the present dt. Control of mutul confoundg between mjor energygenertg nutrients hs modest effect on

6 Diet nd Peripherl Arteril Disese 29 TABLE 5. Multiple logistic regression-derived odds rtios (OR) of peripherl rteril occlusive disese nd 95% confidence tervls (Cl) ssocited with 100-kcl per dy crese of tke of mjor energy-genertg nutrients*: Athens, Greece, 1988 Nutrient OR 95% Cl p vlue (two tiled) Sturted ft Monounsturted ft Polyunsturted ft Totl crbohydrtes Prote * All odds rtios re djusted mutully nd for the core vribles sex, ge, yers of schoolg, smokg hbits, lcohol tke, coffee drkg, nd Quetelet's dex. the estimted odds rtios. Thus, tke of totl crbohydrtes nd polyunsturted fts rems protective, tke of prote rems detrimentl, nd tke of monounsturted ft rems neutrl with respect to the risk of peripherl rteril occlusive disese; only tke of sturted ft becomes sttisticlly nonsignificnt while remg positive risk fctor for the disese. In this model, the regression coefficients llow descriptive mutul comprisons. However, tervl estimtes of the differences between ny two regression coefficients nd ssocited sttisticl testg re not possible without usg more elborte procedures. In this nd other models tht cluded dietry vribles, cigrette smokg nd lcohol consumption remed significnt predictors of peripherl rteril occlusive disese, dictg tht their effects were not ccounted for by differences diet mong smokers nd lcohol drkers. DISCUSSION This study hs three shortcomgs (16): Ptients with peripherl rteril occlusive disese were not nd could not be clerly defble "cident" cses; the cse-control study ws not popultion bsed the trditionl sense; nd cholesterol vlues were not vilble for the comprison ptients for prcticl resons. However, the short-term ftlity of peripherl rteril occlusive disese is low compred with the short-term ftlity of coronry hert disese, where sudden deth cn troduce potentilly serious selection bis cse-control studies; known or suspected selection fctors for hospitliztion (i.e., ge, sex, socioeconomic sttus s reflected yers of schoolg, cigrette smokg, nd lcohol consumption) were ccounted for the nlysis; nd cholesterol, even if vilble, would not hve been controlled the nlysis, sce it represents likely pthwy the cusl lk between diet nd peripherl rteril occlusive disese. Nevertheless, the possibility of selection or recll bis cnnot be completely elimted study of this design; hence, the reltions we found should be exmed other popultions. On the positive side, the study ws conducted with food frequency questionnire tht hs been used numerous studies, nd the nlysis ws undertken tkg to ccount new methodologicl developments (19, 21-23). Results of the present study support the hypothesis tht diet high sturted ftty cids, cholesterol, nd protes creses the risk of therosclerotic disese, wheres diet high polyunsturted ftty cids nd dietry fiber reduces this risk; deed, the ssocitions pper comptible with those predicted on the bsis of Keys equtions (14). Monounsturted ftty cids n isocloric diet do not mterilly ffect the risk of peripherl rteril occlusive disese, but if they re substituted for sturted ftty cids they should hve beneficil effect by elimtg the detrimentl effects of sturted fts. It is difficult to stte whether protes, dietry cholesterol, nd sturted fts hve dependent or convergg effects, or even whether residul confoundg is prtly responsible for one or more of the reltions noted this study. It should be noted, however, tht dietry cholesterol hs been found to be therogenic humns even when serum totl cholesterol is kept reltively constnt the nlysis (24). The pprent protective effect of vitm C ws found to be dependent of its correltion with dietry fiber. Vitm C nd other ntioxidnts re hypothesized to pro-

7 Ktsouynni et l. tect the rteril endothelium from dmge (25) nd to hibit the corportion of cholesterol to mcrophges the rteril tim (26). Vitm C levels blood were versely relted to the degree of coronry rtery occlusion mong ptients evluted by ngiogrphy (27). Olive oil is defed s the oil obted from the fruit of the olive tree (Ole europe Stiv) to the exclusion of oil obted by solvent or reesterifiction processes nd ny mixture with oils of other kds (28). Accordg to the Recommended Interntionl Stndrd for Olive Oil, Virg nd Refed, the ftty cids composition (percentge (mol/mol) of methyl esters) is defed s follows: oleic cid ( ), plmitic cid ( ), loleic cid ( ), steric cid ( ), plmitoleic cid ( ), lolenic cid ( ), myristic cid ( ), nd other ftty cids mute mounts. Olive oil represents n importnt component of the Greek diet (20) nd, more generlly, of the Mediterrnen diet. The results of the present study dicte tht olive oil, the primry source of monounsturted ft, occupies n termedite position between polyunsturted nd sturted fts reltion to peripherl therosclerosis. To the extent, however, tht olive oil substitutes for sturted fts food, diet rich olive oil should be helthier thn diet rich sturted fts. A diet rich polyunsturted ft should be best this context, but there is growg concern tht hbitul tke of lrge quntities of polyunsturtes my not be helthy, sce they promote crcogenesis experimentl nimls nd my hve other undesirble helth effects (29). By contrst, the Mediterrnen diet nd, prticulr, the trditionl Greek diet hve existed for very long time nd been ssocited with some of the lowest overll mortlity ptterns observed lrge humn popultions (15). Our fdgs provide evidence tht the trditionl Mediterrnen diet contributes to the low rtes of crdiovsculr disese southern Europe nd support the hypothesis tht diets high niml products contg substntil mounts of sturted ft nd cholesterol re prtly responsible for the high rtes of therosclerotic disese Western popultions. REFERENCES 1. Ross R. The pthogenesis of therosclerosis n updte. N Engl J Med 1986;4: Dowie R. Generl prctitioners nd consultnts. London: Kg Edwrd's Hospitl Fund, Hull FM, Westermn RF. Referrl to medicl outptient deprtments t techg hospitls Birmghm nd Amsterdm. BMJ I986;293: Fowkes FGR. Aetiology of peripherl therosclerosis. Smokg seems especilly importnt. BMJ 1989;298: The Poolg Project Reserch Group. Reltionship of blood pressure, serum cholesterol, smokg hbits, reltive weight, nd ECG bnormlities to cidence of mjor coronry events: fl report of the poolg project. J Chronic Dis 1978,: Consensus conference: lowerg blood cholesterol to prevent hert disese. JAMA 1985,253: Gordon T, Kgn A, Grci-Plmieri M, et l. Diet nd its reltion to coronry hert disese nd deth three popultions. Circultion 1981,63: Shekelle RB, Shryock AM, Pul O, et l. Diet, serum cholesterol, nd deth from coronry hert disese. N Engl J Med 1981;4: Arntzenius AC, Kromhout D, Brth JD, et l. Diet, lipoprotes, nd the progression of coronry therosclerosis. N Engl J Med 1985;2: Kushi LH, Lew RA, Stre FJ, et l. Diet nd 20- yer mortlity from coronry hert disese. N Engl JMed I985;2: Ahrens EH. The diet-hert question 1985: hs it relly been settled? Lncet 1985; 1: Blnkenhorn DH. Two new diet-hert studies. N Engl JMed 1985;2: Kromhout D, Bosschieter EB, Coulnder CL. The verse reltion between fish consumption nd 20- yer mortlity from coronry hert disese. N Engl J Med I985;2: Keys A. Seven countries. A multivrite nlysis of deth nd coronry hert disese. Cmbridge, MA: Hrvrd University Press, 1980: World Helth Orgniztion. World helth sttistics. Vol I. Genev: WHO, Sklkidis Y, Ktsouynni K, Petridou E, et l. Risk fctors of peripherl rteril occlusive disese: cse-control study Greece. Int J Epidemiol 1989; 18: Grhm S, Dyl H, Swnson M, et l. Diet the epidemiology of cncer of the colon nd rectum. J Ntl Cncer Inst 1978,61: Dles LG, Friedmn GD, Ury HK, et l. A csecontrol study of reltionships of diet nd other trits to colorectl cncer Americn blcks. Am J Epidemiol 1979; 109: Trichopoulos D, Ournos G, Dy NE, et l. Diet nd cncer of the stomch: cse-control study Greece. Int J Cncer 1985;36: Polychronopoulou-Trichopoulou A. Composition of Greek foods nd recipes. Athens: Prisinos, Willett W, Stmpfer MJ. Totl energy tke: im-

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