Br Heart3 1993;70:524-529

Linoleic acid and risk of sudden cardiac death

T L Roberts, D A Wood, R A4:kiemersma, P J Gallagher, F C Lampe

.I-.

AbstractObjective-To test the hypothesis thatthe essential fatty acid, linoleic acid,measured in adipose tissue as an indica-tor of long term dietary intake, isinversely related to the risk of suddencardiac death.Design-A population case-control study.Setting-A regional health district.Subjects-84 men (age 25-64 years) whodied instantaneously or within 24 hoursof the onset of symptoms with no historyof coronary heart disease or medicallytreated hyperlipidaemia, and in whomcoronary artery disease was diagnosed atpostmortem examination as the primarycause of death, were compared with 292age (to within two years) and sexmatched healthy controls and their part-ners drawn from the general practition-ers' records with whom the cases wereregistered.Main outcome measures-Fatty acidcomposition of adipose tissue and therisk ofsudden cardiac death.Results-Linoleic acid in adipose tissuewas inversely related to the risk of sud-den cardiac death. The estimated rela-tive risk (95% CI) of sudden cardiacdeath was 5*7 (1.8 to 17.9) for the lowestquintile and 4*0 (1.2 to 12.9) for the nextquintile of adipose linoleic acid in thecontrol population when compared withthe highest quintile. This inverse relationwas independent of age, reported smok-ing habits, history of hypertension, anddiabetes, although there was a closeassociation with cigarette smoking.The estimated adjusted proportionateincrease in risk (95% CI) of sudden car-diac death was 1-14 (1-03 to 1.23) forevery 1% reduction of linoleic acid inadipose tissue.Conclusions-The percentage content oflinoleic acid in adipose tissue wasinversely related to the risk of suddencardiac death. Populations with a highrisk of sudden cardiac death may benefitfrom increasing their dietary intake ofpolyunsaturated fatty acid oils, princi-pally from cereals and vegetables.

(Br HeartJ_ 1993;70:524-529)

Sinclair first put forward the hypothesis that achronic relative deficiency of polyenoic essen-tial fatty acids, in particular linoleic acid, wasa cause of coronary thrombosis.' Linoleic acid

is essential because it cannot be synthesisedby humans; the only source is our diet. Wehave investigated the relation between linoleicacid, measured in adipose tissue as an indica-tor of long term dietary intake, and the risk ofcoronary heart disease in several populationstudies.2 Cross cultural comparisons ofhealthy middle aged men in populations withdifferent coronary mortality-namely, Fin-land, Scotland, Sweden, and Italy-have con-sistently shown lower frequency distributionsof this fatty acid in countries with a high mor-tality,34 and a between population study ofmiddle aged men and women in Scotland hasalso shown an inverse correlation betweenlinoleic acid in adipose tissue and standard-ised mortality ratios for coronary heart dis-ease in different districts.5 An inverse relationbetween adipose linoleic acid and the risk ofacute myocardial infarction and angina pec-toris has also been found for men with athreefold increase in risk for each of thesenon-fatal manifestations of the disease in thelowest quintile of distribution of linoleic acidwithin populations.67 These inverse relationsare independent of the major risk factors forcoronary heart disease although there was aclose association with smoking as cigarettesmokers eat significantly less linoleic acid andhad correspondingly lower proportionatestorage of this fatty acid compared with non-smokers.7 We now report the relationbetween linoleic, and other fatty acids, andthe risk of sudden cardiac death.

Patients and methodsSELECTION OF CASES OF SUDDEN CARDIACDEATHAll men aged 25-64 years resident in theSouthampton and South West HampshireHealth District (population in 1990 was104 457 in this age and sex group) who diedinstantaneously or within 24 hours of theonset of symptoms were considered. Thosewith no history of coronary heart disease(diagnosis of angina, myocardial infarction,or coronary artery revascularisation) or med-ically treated hyperlipidaemia were eligible forthe study, if coronary artery disease was diag-nosed as the primary cause of death at post-mortem examination. With the assistance ofHM Coroner's office and the Departnentof Pathology, Southampton UniversityHospitals, which together are responsible forall coroners' postmortem examinations, com-munity deaths were monitored and all casesof incident sudden cardiac death identified.

PreventiveCardiology,Department ofMedicineT L RobertsDepartment ofPathologyP J GallagherMedical Statistics andComputing,University ofSouthamptonF C LampeCardiovascularResearch Unit,University ofEdinburghR A RiemersmaClinicalEpidemiology,National Heart andLung Institute,University ofLondonD A WoodCorrespondence toProfessor D A Wood,Clinical Epidemiology,National Heart and LungInstitute. Dovehouse Street,London SW3 6LY.Accepted for publication26 May 1993

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Cases were also identified through surveil-lance of the accident and emergency depart-ment and medical wards at SouthamptonGeneral Hospital and the coronary care unitand medical wards at the Royal SouthHampshire Hospital for deaths in hospital.The 84 cases of sudden cardiac death that

met the criteria were identified between 1January 1990 and 31 July 1991 and in 66(78 6%) adipose tissue samples were takenfrom the anterior abdominal wall at post-mortem examinations and until analysisstored at -70°C. In 14 cases samples weremissed and in four cases the bodies wereseverely decomposed.The coroner's officer interviewed a relative,

bystander, or neighbour in 81 (96&4%) casesand a relative was identified in 78 (92 9%),from whom he obtained the information onname, date of birth, marital state, occupation,and address of the deceased, together withplace, time, and circumstances of death, hismedical history, and medication. The generalpractitioner with whom the deceased was reg-istered was approached and permissionsought to interview the nearest surviving rela-tive. Of the 78 relatives 64 were married part-ners, five were divorcees, and nine bloodrelatives (two mothers, five siblings, and twodaughters). The 40 (51 3%) relatives or othercontacts interviewed were 33 married part-ners, one mother, four siblings, and twodaughters. Two others were interviewed.They were a long-term friend and a landladyof one of the deceased. Twenty six relativesrefused interviews or could not be contacted.In 12 cases the general practitioner refusedpermission to approach the relative.Information was obtained on the deceased'smedical history, smoking habit, alcohol con-sumption, and family history of heart disease.

SELECTION OF CONTROLSControls were selected from the HampshireFamily Practitioner Committee's comput-erised patient register. For each case of sud-den cardiac death four male controlsfrequency matched for age (within two years)were drawn from the records of the generalpractitioner with whom the case was regis-tered with the object of interviewing two con-trols for every case. The 71 1 controls selectedwere checked by their general practitionerand after 25 medical exclusions for psychoticor terminal illness. 686 were contacted by let-ter and invited, together with their partner, tothe preventive cardiology clinic (Royal SouthHampshire Hospital) for a health check. Fiftyone letters were returned by the Post Officeas "not known at this address", 61 refused,and 224 did not attend. Of the 358 (responserate 52%) male controls that were seen, 292(82.0%) attended with their married partners.To validate the female partner's report of theman's demographic details, medical history,smoling habit, alcohol consumption, andfamily history of heart disease, male controlsand their partners were interviewed indepen-dently by the same physician (TLR). In themen, height, weight, and waist and hip cir-

cumference were measured while they werelightly clothed. Sitting blood pressure wasmeasured in the left arm after five minutesrest with diastolic pressure measured at phaseV (Hawksley random zero sphygmomanome-ter). A non-fasting sample of blood was takenby vacutainer, centrifuged, and aliquots ofserum and plasma were stored at -70°C.Adipose tissue was sampled from 292(82.0%) male controls under local anaes-thetic (2% lignocaine) from the anteriorabdominal wall with syringe suction througha 16 gauge needle, washed in a freshly pre-pared 1% solution of vitamin C in normalsaline, and stored at - 70°C. Thirty two con-trols refused to give a sample. Thirty subjectsreported a history of coronary heart disease atthe health check and were therefore not askedto give a sample. Therefore, 230 (64 6%)male controls had adipose tissue sampled andquestionnaires were answered by themselvesand their wives.

LABORATORY PROCEDURESAll laboratory analyses were performed by thecardiovascular research unit and the staffwere not aware whether the samples werefrom cases or controls.The samples of adipose tissue were

thawed, rinsed in saline, and the lipids wereextracted into distilled heptane. This extractwas then washed with isopropanol (0 05%) inpotassium hydroxide (w/v) to remove non-esterfied fatty acids and phospholipids. Theneutral lipid extract was reduced to drynessunder vacuum and dissolved in toluene. Fattyacid methyl esters were prepared by directtransmethylation (10 minutes at 50°C with0 5 M sodium methoxide in methanol). Theesters were washed with acidified water, andre-extracted into hexane, and the hexanelayer evaporated under vacuum. The methylesters were redissolved in 40 jl redistilledcholoroform for analysis on a PyeChromatograph 204. This was fitted with a1-5 m column packed with GP 10% SP-2330on 100/120 mesh Chromosorb WAW(Supelco). The peaks were quantified with aflame ionisation detector and Perkin ElmerNelson integrator. The retention times ofauthentic fatty acid methyl esters were usedfor identification.

STATISTICAL ANALYSISThe mean proportion of linoleic acid in adi-pose tissue in men from our previous surveysallowed us to estimate that 75 cases and 150controls would be required to detect a differ-ence of 0 34 of a standard deviation at thep < 0 05 level of significance in a two sidedtest with 80% power.

Comparisons between cases and controlswere made with non-parametric tests. TheMann-Whitney U test was used for compar-isons of continuous variables and the X2 (withcontinuity correction) for categorical data. Alogistic regression was used to assess the inde-pendent contribution of linoleic acid in adi-pose tissue and other risk factors of coronaryheart disease to the risk of sudden cardiac

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death, in a stepwise procedure, with a cut offof p = 0.05. The significance of each factorincluded in the model was tested by means ofthe likelihood ratio statistic. Adjusted oddsratios with 95% confidence intervals (95%CIs) were calculated. The analysis was car-ried out with the logistic, regression procedurein SPSS v4 on an IBM 3090 mainframe com-puter.The data from risk factors of coronary

heart disease used in the regression analyseswere obtained from the relatives of controls.Agreement between responses of controls andtheir spouses was tested with the Kappastatistic. For the cases, information fromrelatives and coroners officers was used,or from 'coroners' officers only when norelatives were interviewed. The records of thecoroners' officers were incomplete for smok-ing habit, but six cases were confirmed assmokers in addition to those confirmed byrelatives.The study was approved by the

Southampton and South West HampshireDistrict Health Authority Ethics Committee(submission number 103/87).

ResultsCASES OF SUDDEN CARDIAC DEATHThe 84 cases of sudden cardiac death identi-fied had a mean age of 54-9 (range 33-64)years and 68 (809%) died in the community,55 at home, 16 in hospital, and 13 elsewhere(six at work, four in a public place, two in pri-vate cars and one at another person's homr).Deaths showed no temporal pattern by timeof day, day of the week, and month of theyear. Thirty nine (46A4%) deaths were wit-nessed and in 13 (33 3%) death was instanta-neous. For the 42 cases of sudden cardiacdeath where relatives were interviewed 33(78 5%) had one or more symptoms beforedeath and 26 (61-9%) of these had chestpain. Twenty two (52 4%) were taking one ormore drugs before death. Table 1 shows thepathological findings at postmortem examina-tion.

Cases of sudden cardiac death with andwithout adipose samples did not differ signifi-cantly in age, time of day, day of the week ormonth of death, place of death, and whetherthe death was witnessed or not. Nor was the

Table 1 Postmortem examination results in 84 cases ofsudden cardiac death

No (/qo)

Severity of coronary artery disease*.Mild 3 (3.6)Moderate 21 (25 0)Severe 59 (70 2)

Coronary artery thrombus 35 (41-7)

Macroscopic evidence of:Acute infarction 27 (32-1)Old infarction 22 (26 2)

Left ventricular:Hypertrophy 45 (53 6)Dilatation 7 (8-3)Rupture 3 (3.6)

Mean heart weight (g) (range) 438 (286-740)*1 case not classifiable.

proportion with relatives identified and inter-viewed different. Smoking habit, diabetes,alcohol consumption, medication, and familyhistory of premature (<60 years) coronaryheart disease did not differ between thosewith and without samples but a history ofhypertension was significantly more commonin those who were not sampled. Heart weight,prevalence of thrombus, acute infarction, oldinfarction, and left ventricular hypertrophywere not significantly different between thegroups.

ADIPOSE FATTY ACID COMPOSITIONCases of sudden cardiac death had signifi-cantly lower linoleic acid (C 18:2) comparedwith controls (table 2). Cases also had signifi-cantly lower palmitic (C 16:0), and higherpalmitoleic (C16:1), oleic (C18:1), gondoic(C20:1), and eicosadienoic (C20:2n-6) acidcompared with controls. Total saturated andpolyunsatured fatty acids were significantlylower in cases, and monounsaturated acidssignificantly higher in cases, but there was nodifference between cases and controls in theratio of polyunsaturated: saturated fatty acids.

RISK FACTORS. REPORTED BY PARTNERSAgreement -letween male controls and theirmarried pgrtners on the man's smoking habit(Kappa O688), medically treated hypertension(Kappt 0*92), and diabetes (Kappa 0 85) wasstrg with only a small number of misclassi-fi%tions.

Reported cigarette smoking by the partners,of the victims of sudden cardiac death wassignificantly more prevalent than by controlpartners (table 3). Ex-cigarette smokers andlifelong non-smokers were also more com-mon in the controls. A family history of pre-mature heart disease (<60 years) in a firstdegree relative was three times more likely invictims of sudden cardiac death, but therewas no difference in the proportion of eithermedically treated hypertension or diabetesbetween cases and controls.

LINOLEIC ACID AND THE ESTIMATED RELATIVERISK OF SUDDEN CARDIAC DEATHThe contribution of adipose linoleic acid tothe risk of sudden cardiac death was esti-mated with stepwise logistic regression. Withsudden cardiac death as the dependent vari-able the analysis used age, current cigarettesmoking reported by relatives or coroner'sofficer, history of treated hypertension, his-tory of treated diabetes, and adipose linoleicacid in 65 cases and 230 controls with com-plete data. Linoleic acid (X2 = 9 11; p = 0 03)made a significant and independent contribu-tion to the explanation of sudden cardiacdeath together with smoking habit.

Table 4 shows the estimated unadjustedand adjusted relative risks and 95% CIs ofsudden cardiac death by quintiles of distribu-tion of adipose linoleic acid in the controlpopulation. The estimated unadjusted pro-portionate increase in risk (95% CI) of sud-den cardiac death was 1-16 (1-06 to 1-27),and after adjustment for the above coronary

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Table 2 Mean percentage (SEM) of adipose tissue fatty acids in healthy controls andcases ofsudden cardiac death

Sudden cardiac ControlsFatty acidst death (n = 66) (n = 292)

Saturated:Myristic C14:0 3-35 (0-10) 3-30 (0-04)Palmitic C16:0 21.5** (0-28) 22-1 (0-12)Stearic C18:0 4-65 (0 16) 4-89 (0-06)Total 29.5** (0 45) 30 3 (0-17)

Monounsaturated:Palmitoleic C16:1n-7 6.79** (0-24) 5-95 (0-09)Oleic C18:1n-9 46.9** (0-30) 45-9 (0-14)Gondoic C20:1n-9 2-30** (0-08) 2-04 (0-03)Total 56 0** (0 48) 53-9 (0-20)

Polyunsaturated:a-Linolenic C18:3n-3* 0 73 (0-03) 0-76 (0-01)Docosapentaenoic C22:5n-3 0-19 (0-01) 0-18 (0-003)Docosahexaenoic C22:6n-3 0-13 (0-01) 0-14 (0-01)Linoleic C18:2n-6 11-2** (0-41) 12-1 (0-23)y-Linolenic C18:3n-6§ 0-32 (0-02) 0-29 (0-01)Eicosadienoic C20:2n-6 0-28* (0-02) 0-24 (0-01)Dihomo-yLinolenic C20:3n-6 0-13 (0-01) 0-13 (0-004)Arachidonic C20:4n-6 0-32 (0-01) 0-30 (0-01)Docosatetraenoic C22:4n-6 0-09 (0-01) 0-08 (0-002)Total 13 1* (0-43) 14-5 (0-24)

Ratio of Polyunsaturated: 0-45 (0-02) 0-49 (0.01)saturated

*p < 0-05; **p < 0-01; Mann-Whimey U test. tShorthand notation: C carbon atoms followedby number of double bonds, and the position of the double bond closest to the terminal methylcarbon atom (n-x). tComplex peak including C20:ln-1 1. §Complex peak including C20:0.

Table 3 Risk factors ofcoronary heart disease in healthycontrols and cases ofsudden cardiac death

Controls Cases(from relatives) (from relatives)(n = 292) (n = 42)

Age (SD) (y) 57-2 (6-7) 56-4 (7-6)

Smoling (%):Never stoked 73 (25-0) 4 (9.5)*Ex-smoker 139 (47-6) 7 (16-7)**Pipeorcigar 11(3-8) 3(7-1)Current cigarette 69 (23-6) 28 (66-7)***

Medical history (%):Treated hypertension 39 (13-4) 7 (16-7)Diabetes mellitus 11 (3-8) 1 (2-4)

History of heart diseasein first degree relative<60 yr (%) 30 (10-3) 15 (35-7)***

*p<0-05, **p < 0-01,***p < 0001; X2 test.

heart disease risk factors was 1-14 (1-03 to1-23), for every 1% reduction in adiposelinoleic acid.With sudden cardiac death as the depen-

dent variable a second regression analysis wasperformed with age, history of treated hyper-tension and diabetes, and adipose linoleicacid, but with the assumption that all cases ofsudden cardiac death, with smoking informa-tion missing (n = 17), were current cigarettesmokers. Smoking x2 = 78-3; p = 0-0001) was

the only factor to make a significant and inde-pendent contribution to the risk of suddencardiac death.

DiscussionThe risk of sudden cardiac death in this pop-ulation is strongly and inversely related toadipose linoleic acid and this is consistentwith our previous reports of a similar associa-tion with both acute myocardial infarctionand, angina pectoris.6n This inverse relationwith sudden cardiac death is independent ofthose risk factors of coronary heart disease(CAD) that could be measured retrospec-tively, but is closely associated with smokingcigarettes. Sinclair first postulated a chronicrelative deficiency of polyenoic essential fattyacids, of which linoleic acid is the common-

est, as a cause of coronary thrombosis.'Clinical studies subsequently reported thatpatients with atherosclerosis (coronary arterydisease, peripheral arterial disease, and cere-

brovascular disease) had lower concentrationsof linoleic acid in their blood lipid fractionsand adipose tissue than controls.8

In our cross cultural studies populationswith a high coronary mortality (Scotland andFinland) had significantly lower distributionsof adipose linoleic acid in middle agedhealthy men than countries (Sweden andItaly) with a lower coronary mortality.34Within Scotland there is an inverse relationbetween mean adipose linoleic acid in men

and women and the standardised mortalityratios for CHD in different districts.5 Theprevalence of CHD among men in a popula-tion survey on the east coast of Scotland,diagnosed at the time of examination, was

also inversely related to adipose linoleic acid.6Nearly a quarter of all cases of CHD in thisstudy were found in the bottom decile of adi-pose linoleic acid in the healthy population. Asubsequent population case-control studyfound a threefold risk of angina pectoris andacute myocardial infarction when comparingthe lowest and highest quintiles of adiposelinoleic acid in the control population, andthese inverse relations were independent ofthe major risk factors of CHD, at least forangina, although there was a close associationwith smoking, which confounded the relationwith myocardial infarction.7 Only one

prospective population (case-control) study offatty acids has been reported. In this,Miettinen et al estimated the fatty acid com-

position of phospholipids, cholesterol esters,

Table 4 Relative unadjusted and adjusted risks (95% CIs) ofsudden cardiac death by adipose linoleic acid composition

Quintites % of linoleic acid

1 (<9-5) 2 (9-5 < 11-5) 3 (11-5 < 13-0) 4 (13-0 < 15-7) 5 (15-7)

Cases (n = 65) 23 16 10 12 4Controls (n = 230) 46 46 46 46 46Unadjusted odds ratio 5-7 4-0 2-5 3-0 1

(95% CI) (1-8 to 17-9) (1-2 to 12-9) (0-7 to 8-5) (0-9 to 9-9)Adjustedt odds ratio (95% CI) 4-4 3-5 2-4 3-0 1

(1-4 to 14-1) (1-1 to 11-5) (0-7 to 8-3) (0-9 to 10-0)

tAdjusted for age, current cigarette smoking, history of treatment for hypertension or diabetes.

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and triglycerides from fasting serum.9 Casesof non-fatal and fatal myocardial infarctionand sudden death had a significantly lowerconcentration of linoleic acid, and lower totalpolyunsaturated fatty acids in phospholipidsbut not cholesterol esters, than in controls.This relation was only significant for those inthe lowest quintile of fatty acid distributionbut was independent of age, smoking, bloodpressure, cholesterol and triglyceride concen-trations, obesity, and glucose tolerance.Two other surveys of populations at

necropsy have examined the composition ofadipose fatty acids and its relation to deathfrom CHD. Thomas and Scott studiednecropsies drawn from 10 areas in Englandand Wales and found that adipose linoleicacid was almost identical in the cases of deathattributed to CHD and to other causes.'0 Inthe United States Strong et al compared bothblack and white men who died from CHDwith men who had died from external vio-lence (accident, suicide, or homicide) or anynatural cause other than atherosclerotic dis-ease." Again there was no difference in adi-pose linoleic acid in those who died fromCHD or from other causes, regardless of eth-nic origin. Both studies included men with ahistory of CHD before death, who mighthave increased their consumption of polyun-saturated fats, thus potentially obscuring areal difference in linoleic acid. In our dietarysurvey men with a reported diagnosis ofCHD (either myocardial infarction or anginapectoris) did have a higher dietary intake oflinoleic acid, and a correspondingly higheradipose concentration compared with thosein whom we made the diagnosis.6 This differ-ence in linoleic acid is consistent with dietarychange after diagnosis and is an importantconservative bias in retrospective studies. Inthis study the men had no medical diagnosisof CHD before death and deaths were instan-taneous, or within 24 hours of the onset ofsymptoms. So unlike previous population sur-veys this potential dietary bias does not exist,and the extent to which the victims of suddencardiac death changed their diets after a diag-nosis of systemic hypertension or diabetescould only underestimate the strength of therelation we have found between linoleic acidand sudden cardiac death.

In animal experiments diets rich in linoleicacid reduce the incidence of serious ventricu-lar arrhythmias induced by coronary ligationin vivo. A strong inverse relation was foundbetween adipose linoleic acid (r = -0.92) andthe frequency of ischaemic ventricular fibrilla-tion in rats feeding a diet with polyunsatu-rated:saturated fatty acid ratio of 2 for onlyfour weeks.12 In a longer term experiment theincidence of ventricular tachycardia and fib-rillation was significantly lower in rats fedwith a supplement of sunflower seed oil forup to 20 months compared with a referencediet. Even after long-term feeding of satu-rated animal fatty acids the incidence of ven-tricular fibrillation both on coronary arteryocclusion and reperfusion was significantlyreduced by supplementing the rats' diet with

sunflower seed oil.13 This is consistent withlinoleic acid having a protective effect againstthese arrhythmias."4 Although there havebeen no dietary experiments in humans basedon a linoleic acid supplement alone, the Osloprimary prevention trial in high risk middleaged men, which used a low saturated highpolyunsaturated fatty acid diet, showed a sig-nificantly lower incidence of sudden cardiacdeath in the experimental group.'5

Although this inverse relation betweenlinoleic acid and sudden cardiac death is con-sistent with our previous studies of non-fatalmanifestations of this disease cautious inter-pretation is required. There is a stronginverse association between smoking andconsumption of linoleic acid and thereforeexposure to tobacco could be the real causeand diet a chance association. Alternatively,the relation between smoking cigarettes andCHD, which is largely unexplained except fora higher fibrinogen concentration in smokers,might be partly due to differences in thedietary habits of smokers and non-smokers.Smokers eat less polyunsaturated fatty acids,and in particular less linoleic acid, and thisdietary preference, possibly reflecting differ-ences in taste, may be an important determi-nant of coronary risk in smokers rather thantobacco itself.'0 It is not possible to separateout these interrelations any further with epi-demiological data, but the dietary habits ofnon-smokers and how these change whensomeone takes up smoking, or converselystops the habit, requires investigation. Aswith any retrospective study fatty acid com-position of adipose tissue may reflect changesthat result from dying and not the patternbefore death, but animal experimental evi-dence suggests the relative fatty acid distribu-tion remains the same after death for at least36 hours (R Riemersma, personal communi-cation). Samples of adipose tissue are incom-plete among cases and those missed may havea different composition, but given the similar-ity in other characteristics of those not sam-pled, this seems unlikely.The response rate of healthy controls was

low and whereas this partly reflects comput-erised Family Health Service Authority prac-tice lists containing patients who have died,moved away, or are no longer registered, italso represents a true non-response that mayintroduce bias. Controls who are more mid-dle class and health conscious are likely tohave a higher intake of linoleic acid. Thiscould exaggerate the risk of sudden cardiacdeath associated with lack of this fatty acidbut this bias cannot be quantified in ourstudy. Although the response rate of healthycontrols is low they are, unlike dead controls,without manifest disease and therefore dietaryhabits are unlikely to have changed. Theywere also unselected, except for non-response, and therefore give a more represen-tative picture of the distribution of linoleicacid in middle aged men than dead controls.The measurement of exposure to risk fac-

tors of CHD is incomplete for smoking andunobtainable for blood pressure and lipid

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concentrations. If all cases of sudden cardiacdeath are assumed to be cigarette smokersthen tobacco exposure emerges as the onlystatistically significant factor for suddendeath, but even if this assumption were true itdoes not preclude smoking from operatingthrough dietary preferences to increase therisk of an arrhythmic death."314 Whether therelation between linoleic acid and sudden car-diac death could be modified by other riskfactors in the model is not known, but asblood pressure is only weakly and inverselyassociated with adipose linoleic acid, andlipids show no strong associations with thisfatty acid,7 this seems unlikely. In theprospective study of Miettinen et al the rela-tion between linoleic acid in phospholipidsand all manifestations of CHD takentogether, including death from CHD, wasindependent of all major risk factors ofCHD.9Our finding of an inverse relation between

adipose linoleic acid and the risk of suddencardiac death is consistent with that alreadyshown for both acute myocardial infarctionand angina pectoris,7 and the scientific evi-dence for causality is strengthened throughshowing these relations in different popula-tions, at different times, and separately for themajor clinical manifestations of CHD.A7 Themost likely explanation for these findings isthat men who choose diets poor in linoleicacid predispose themselves to the develop-ment of angina pectoris, myocardial infarc-tion, and sudden cardiac death. Theproportionate storage of linoleic acid in adi-pose tissue is largely determined by long-termdietary intake, and therefore provides aunique retrospective measure of consumptionof this essential fatty acid in victims of suddencardiac death, although other explanationssuch as differences in absorption, fatty acidmetabolism, and storage of linoleic acid can-not be excluded.The Committee on Medical Aspects of

Food Policy reporting on diet and cardiovas-cular disease in the United Kingdom recom-mended a reduction in total fat, and saturatedfat in particular, but no specific recommenda-tions were made for polyunsaturated fattyacids.'7 We believe the epidemiological, clini-cal, and experimental evidence of an inverserelation between linoleic acid, the principalpolyunsaturated fatty acid, and CHD is nowsufficiently strong to recommend that popula-tions with a high mortality from CHD mightbenefit from supplementing their eatinghabits with more polyunsaturated oils, princi-pally from cereals and vegetables. Althoughcigarette smokers are strongly urged to stop,this dietary recommendation is particularlyimportant for those who cannot, especially

heavy cigarette smokers, who have the lowestintake of this essential fatty acid.

We thank HM Coroner Mr R N MacKean, coroner's officers,consultant pathologists, and mortuary staff of the Departmentof Pathology, Southampton University Hospitals, for theirhelp in the identification of cases of sudden cardiac death andcollection of samples; Karen Lyall and Jacqui Lawrence forfatty acid analyses; the Hampshire Family Health ServicesAuthority for their help in selecting controls; research nursesin the preventive cardiology clinic: Jenny Cole, PatriciaElliott, Rosemary Ogilvie, Barbara Saunders, and FrancesWatts; Christine Bicknell for administration, and all the gen-eral practitioners in Southampton district who so willinglyassisted with this study. TLR had a Merck, Sharp, andDohme lectureship in preventive cardiology. The study wassupported by a grant from the Wellcome Trust (18907/1-5)and the Preventive Cardiology Trust (administrator, MrDennis Urquhart) that administers the Geoffrey Fryerbequest.

1 Sinclair HM. Deficiency of essential fatty acids and ather-osclerosis, etcetra [Letter]. Lancet 1956;1:381-3.

2 Van Staveren WA, Deurenberg P, Katan MB, Burema J,de Groot LCPGM, Hoffmans MDAF. Validity of thefatty acid composition of subcutaneous fat tissue micro-biopsies as an estimate of long term average fatty acidcomposition of the diet of separate individuals. Am JEpidemiol 1986;123:455-63.

3 Logan RL, Riemersma RA, Thomson M, Oliver MF,Olsson AG, Walldius G, et al. Risk factors for ischaemicheart-disease in normal men aged 40. Edinburgh-Stockholm Study. Lancet 1978;i:949-55.

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