Mercury, Fish Oils, and the Risk of Myocardial Infarction
Eliseo Guallar, M.D., Dr.P.H., M. Inmaculada Sanz-Gallardo, M.D., M.P.H., Pieter van't Veer, Ph.D., Peter Bode, Ph.D., Antti Aro, M.D., Ph.D., Jorge Gómez-Aracena, M.D., Ph.D., Jeremy D. Kark, M.D., Ph.D., Rudolph A. Riemersma, Ph.D., José M. Martín-Moreno, M.D., Dr.P.H., Frans J. Kok, Ph.D., for the Heavy Metals and Myocardial Infarction Study Group
Background It has been suggested that mercury, a highly reactiveheavy metal with no known physiologic activity, increases therisk of cardiovascular disease. Because fish intake is a majorsource of exposure to mercury, the mercury content of fish maycounteract the beneficial effects of its n–3 fatty acids.
Methods In a case–control study conducted in eight Europeancountries and Israel, we evaluated the joint association ofmercury levels in toenail clippings and docosahexaenoic acid(C22:6n–3, or DHA) levels in adipose tissue with the riskof a first myocardial infarction among men. The patients were684 men with a first diagnosis of myocardial infarction. Thecontrols were 724 men selected to be representative of the samepopulations.
Results The average toenail mercury level in controls was 0.25µg per gram. After adjustment for the DHA level and coronaryrisk factors, the mercury levels in the patients were 15 percenthigher than those in controls (95 percent confidence interval,5 to 25 percent). The risk-factor–adjusted odds ratiofor myocardial infarction associated with the highest as comparedwith the lowest quintile of mercury was 2.16 (95 percent confidenceinterval, 1.09 to 4.29; P for trend=0.006). After adjustmentfor the mercury level, the DHA level was inversely associatedwith the risk of myocardial infarction (odds ratio for the highestvs. the lowest quintile, 0.59; 95 percent confidence interval,0.30 to 1.19; P for trend=0.02).
Conclusions The toenail mercury level was directly associatedwith the risk of myocardial infarction, and the adipose-tissueDHA level was inversely associated with the risk. High mercurycontent may diminish the cardioprotective effect of fish intake.
Mercury is a highly reactive heavy metal with no known physiologicactivity.1,2 Exposure to toxic levels of mercury results inneurologic and renal damage, but the consequences of long-termexposure to low levels of mercury are poorly understood.1,2Mercury may predispose people to atherosclerotic disease bypromoting the production of free radicals or by inactivatingseveral antioxidant mechanisms through binding to thiol-containingmolecules or to selenium.3,4,5 In 1995, Salonen et al. reportedan increased risk of coronary heart disease among residentsof the Kuopio area in Finland whose hair samples had increasedlevels of mercury.6,7 The participants in that study, however,had relatively high levels of mercury, which were derived largelyfrom locally contaminated freshwater fish.
Fish intake is a major source of exposure to mercury, mainlyin the form of methylmercury.2 Intake of fish or fish oils (long-chainn–3 polyunsaturated fatty acids) has long been hypothesizedto prevent cardiovascular events.8 Two large, randomized clinicaltrials have shown reduced mortality after myocardial infarctionamong patients assigned to a diet rich in fatty fish9 or tofish-oil supplements,10 but the generalizability of these findingsto subjects without coronary heart disease is uncertain. Theresults of epidemiologic studies relating fish intake or fish-oillevels to coronary events have been contradictory,11 and ithas been suggested that mercury may counteract the beneficialcardiovascular effects of n–3 fatty acids in fish.2,6,7
To evaluate the association of mercury with the risk of myocardialinfarction, and to test the hypothesis that high mercury levelsmay offset the inverse association between fish oil consumptionand myocardial infarction, we assessed the joint associationof mercury levels in toenail clippings and docosahexaenoic acid(C22:6n–3, or DHA) levels in adipose tissue with the riskof a first myocardial infarction among men who were participantsin the European Multicenter Case–Control Study on Antioxidants,Myocardial Infarction and Cancer of the Breast (EURAMIC).12,13
Methods
Design and Subjects
The target population consisted of men 70 years of age or youngerwho were native residents of any of eight European countriesor Israel.12,13 Subjects were excluded if they had a previousdiagnosis of myocardial infarction, drug or alcohol abuse, ora major psychiatric disorder; if they were institutionalized;or if they had modified their dietary pattern in the previousyear.
The patients were men with a first acute myocardial infarction(code 410 of the International Classification of Diseases, 9thRevision), confirmed by characteristic electrocardiographicchanges and elevated enzyme levels,14 who had been hospitalizedwithin 24 hours after the onset of symptoms. They were recruitedfrom the coronary care units of participating hospitals.
The controls were men without a history of myocardial infarction,recruited from the population of the catchment areas from whichthe patients originated, and frequency-matched for age in five-yearintervals. In Finland, Israel, Germany, Scotland, and Switzerland,random sampling from local population registers was used toselect controls. In Russia and in the two Spanish centers, populationregistries could not be used, because of the lack of completecensus data or because of legal restrictions. Therefore, controlswere selected from among hospitalized patients with disordersnot known to be associated with dietary factors (renal colic,hernia, acute appendicitis or mesenteric adenitis, volvulusor subocclusion due to fibrosis, noninfectious prostatism, andrectal or anal disorders other than cancer, hemorrhoids, orchronic infections).12 When low participation rates from populationsamples were anticipated, controls were selected by random samplingfrom the catchment area of the patient's general practitioner(in the Netherlands) or by inviting apparently healthy friendsand relatives of the patient to participate (in Norway).12,13
Patients and controls were recruited concurrently during 1991and 1992. The participation rates among potential subjects were81 percent for patients and 64 percent for controls. Local institutionalreview boards approved the study, and written informed consentwas obtained from study participants.
Data Collection
Information on smoking, hypertension, and diabetes was collectedby standard questionnaires.12,13 A history of hypertension ordiabetes was based on the patient's report of a physician'sdiagnosis. A family history of coronary heart disease was definedby a self-reported fatal or nonfatal myocardial infarction ina parent. Clippings from all 10 toenails were collected withineight weeks of enrollment.13 The mean (±SD) weight ofthe samples was 53.8±39.0 mg. A subcutaneous specimenof adipose tissue was taken from the buttock by needle aspiration.12The adipose-tissue sample was taken from patients within sevendays after admission to the hospital. A nonfasting sample ofvenous blood was also obtained. Blood samples were drawn frompatients within 24 hours after hospital admission.
Analysis of Biologic Samples
Toenail mercury was measured by instrumental neutron-activationanalysis at the Interfaculty Reactor Institute of Delft Universityof Technology, Delft, the Netherlands.15 Toenail clippings wereirradiated for four hours in a thermal flux of 5x1012 neutronsper second per square centimeter. After a decay time of 21 days,the gamma radiation of mercury was measured in a well-type Ge(Li)detector for one hour. Irradiation of study samples was conductedfrom April 1998 through June 1999. Samples from patients andcontrols were analyzed together, randomly distributed acrossbatches, and masked with respect to case–control status.
For each sample, the limit of detection was defined as the levelat which mercury could be detected with 97.5 percent certainty.For a sample of average weight (53 mg), the limit of detectionwas 0.11 µg per gram. In the 76 samples with mercury levelsbelow the detection limit, we imputed a mercury level of onehalf the detection limit. For quality control, a sample of freeze-driedplankton reference material (BCR CRM-414, Community Bureau ofReference, Commission of European Communities) was includedin each analytic batch. The average of 48 measurements of thismaterial was 0.26 µg per gram (95 percent confidence interval,0.24 to 0.28), against a certified mercury level of 0.276±0.018µg per gram. The interassay coefficient of variation forthis reference material was 13.6 percent.
Fatty acids in adipose tissue were assayed at the National PublicHealth Institute, Helsinki, Finland, by gas chromatography (modelHRCG412, HNU Nordion Oy).16,17 The portion of the fatty-acidpeak area containing DHA, as determined by gas chromatography,was calculated and expressed as a fraction of the total fatty-acidpeak area. Because the levels of eicosapentaenoic acid (C20:5n–3)in adipose tissue were below the detection limit of the chromatographfor most samples, fish-oil fatty acids were represented exclusivelyby DHA.18 The interassay coefficient of variation for DHA inadipose tissue was 25 percent. The serum total cholesterol levelswere determined by standard methods.12
Statistical Analysis
Because the distribution of mercury was right-skewed, logarithmictransformation was used to improve normality. The distributionof mercury in controls was used to compute cutoff points andmedians for quintiles of exposure. For multivariate analysis,the association of mercury with the risk of myocardial infarctionwas estimated by multiple logistic regression. The odds ratiosin quintiles 2, 3, 4, and 5 were estimated by using the lowestquintile as the reference category, and tests for trend acrossquintiles of mercury were performed. The reported P values aretwo-tailed. Statistical analyses were performed with S-Plussoftware.19
Results
In comparison with the controls, the patients had significantlyhigher body-mass index and lower high-density lipoprotein cholesterollevels and were more likely to have hypertension, to have diabetes,to smoke, and to have a family history of myocardial infarction(Table 1).12 The total cholesterol level was lower among patientsthan among controls, almost certainly reflecting the effectof acute myocardial infarction. Therefore, total cholesterolwas not further considered in case–control comparisons.
Table 1. Cardiovascular Risk Factors in Patients with Myocardial Infarction and in Controls.
Controls from Zeist, the Netherlands, and Berlin, Germany, hadthe lowest average levels of mercury among controls (0.14 and0.17 µg per gram, respectively), whereas those from thetwo Spanish centers had the highest (0.57 µg per gramin Granada and 0.51 µg per gram in Málaga) —a 4.1-fold range of variation (Table 2). The level of DHA inadipose tissue was strongly correlated with the toenail mercurylevel (Table 3). The age- and center-adjusted correlation coefficientbetween the levels of DHA and mercury was 0.34 (P<0.001).
Table 3. Risk Factors According to Quintile of Toenail Mercury Level among Controls, Adjusted for Age and Center.
After adjustment for age, center, and DHA level, the patientshad higher mercury levels than the controls (case–controlratio, 1.10; 95 percent confidence interval, 1.03 to 1.18) (Table 2).This association persisted after the exclusion of the twoSpanish centers, which were the centers with the highest mercurylevels (DHA-adjusted case–control ratio, 1.09; 95 percentconfidence interval, 1.02 to 1.17), and after adjustment formultiple cardiovascular risk factors (case–control ratio,1.15; 95 percent confidence interval, 1.05 to 1.25).
Analysis with adjustment for age and center showed an increasedrisk of myocardial infarction at high mercury levels (P fortrend=0.01) (Table 4). Adjustment for DHA markedly increasedthe association and elicited a graded, positive dose–responsepattern. This trend was further strengthened after adjustmentfor traditional risk factors and levels of antioxidants, resultingin an odds ratio of 2.16 for patients in the highest quintileof mercury level, as compared with the lowest (95 percent confidenceinterval, 1.09 to 4.29; P for trend=0.006). When mercury wasintroduced as a continuous variable in the regression models,the multivariate odds ratio associated with a change from the25th to the 75th percentile of the mercury distribution was1.63 (95 percent confidence interval, 1.22 to 2.18; P=0.001).
Table 4. Odds Ratios for a First Myocardial Infarction, According to Quintile of Toenail Mercury Level or Adipose-Tissue Docosahexaenoic Acid (DHA) Level.
The dose–response curve for the relation between the mercurylevel and the risk of myocardial infarction was further examinedby nonparametric logistic regression (Figure 1).19 There wasa positive, monotonic increase in risk associated with mercurylevels above 0.25 µg per gram, which was steeper afteradjustment for DHA levels.
Figure 1. Nonparametric Estimates of the Risk of Myocardial Infarction According to the Levels of Mercury in the Toenails (Panel A) and of Docosahexaenoic Acid (DHA) in Adipose Tissue (Panel B).
All curves have been adjusted for age and center. The nonparametric regression models used a lowess smoother with 40 percent span.19 The reference value (odds ratio = 1.0) was set at 0.08 µg per gram for mercury and 0.08 percent of the total fatty-acid peak area for DHA, both values corresponding to the 5th percentile of their respective distributions among controls. The bars represent the frequency distribution of mercury and DHA in the study sample.
The average levels of DHA, expressed as a percentage of thetotal fatty-acid peak area, were 0.24±0.13 percent inpatients and 0.25±0.13 percent in controls. In analysesadjusted for age and center, there was no consistent relationbetween increasing DHA levels and the risk of myocardial infarction(Table 4).17 After adjustment for the mercury level as well,there was a significant trend toward a lower risk of myocardialinfarction with higher DHA levels (P for trend = 0.01). Thistrend was confirmed in the nonparametric analyses (Figure 1).There was no interaction between mercury and DHA with respectto their associations with the risk of myocardial infarction(P for the interaction=0.61).
We performed several sensitivity analyses to assess the consistencyof our findings. First, we reanalyzed the data while excludingthe results from Málaga, the center with the strongesteffect of mercury. When we did so, the association of mercurywith the risk of myocardial infarction persisted: the DHA-adjustedcase–control ratio of mercury levels was 1.08 (95 percentconfidence interval, 1.01 to 1.15). In addition, there wereno significant differences in the association of mercury andmyocardial infarction among study centers (P for the interactionbetween center and mercury level=0.20). Second, we found similarresults in centers that used controls from the general populationand in those that selected other types of controls (data notshown). Third, we confirmed that the participation rates ineach center, both for patients and for controls, were not correlatedwith the association between mercury level and myocardial infarction(P=0.66 for the correlation in controls and P=0.97 for the correlationin patients). Finally, we assessed the association between mercurylevel and myocardial infarction, restricting our analyses tothe five centers with the highest response rates among controls;the results were similar to our overall results (the ratio ofthe mercury level in patients relative to that in controls,after adjustment for DHA levels, was 1.12; P=0.005).
Discussion
In this international case–control study, we found anindependent and graded association between toenail mercury levelsand the risk of myocardial infarction. Furthermore, mercurymasked an inverse association between DHA levels and the riskof myocardial infarction that became evident only after adjustmentfor the mercury level.
Several factors add to the strength of our findings. First,toenail and adipose-tissue samples were collected from patientsshortly after they had had a myocardial infarction. These measurementsare therefore unlikely to have been affected by the developmentof disease, a common limitation of case–control studies.Second, only patients with a first myocardial infarction wereexamined, so it is unlikely that they had changed their dietbefore the event. Finally, toenail mercury is a reliable biologicmarker of long-term exposure to mercury.2,20,21 The validityof the mercury measurements in our study is further reinforcedby the finding of a strong association between mercury and DHA,a biologic marker of fatty-fish intake.18
Mercury exists in three forms: elemental mercury, inorganicmercury compounds, and organic mercury, primarily methylmercury.1,2Exposure to inorganic mercury occurs occupationally; peoplecan also be exposed to inorganic mercury from silver–mercuryamalgam in dental fillings. Exposure to methylmercury resultsalmost exclusively from the consumption of fish, shellfish,and marine animals; these foods are a major source of exposureto mercury for the general population.2 Large, predatory fish,such as swordfish and sharks, have the highest concentrationsof mercury (around 1 µg per gram); tuna, trout, pike,and bass have intermediate concentrations (0.1 to 0.5 µgper gram); and most shellfish have low concentrations.1,2 Inpopulations eating large quantities of fish from locally contaminatedlakes or rivers, however, other species may be the main contributorsto the total intake of mercury.6
Mercury may promote atherosclerosis and hence increase the riskof myocardial infarction in several ways. Mercury promotes theproduction of free radicals in experimental models,3,4,5 andit may bind selenium to form mercury selenide, an insolublecomplex that cannot serve as a cofactor for glutathione peroxidase.22In addition, methylmercury has a very high affinity for thiolgroups, and it may inactivate the antioxidant properties ofglutathione, catalase, and superoxide dismutase.23 Mercury mayinduce lipid peroxidation,24 and mercury levels were a strongpredictor of oxidized low-density lipoprotein levels in theKuopio Ischemic Heart Disease Study.6 Mercury compounds mayalso promote platelet aggregability25 and blood coagulability,26inhibit endothelial-cell formation and migration,27 and affectapoptosis and the inflammatory response.28 Increased rates ofcardiovascular disease were found among mercury-exposed workers,29,30and mercury levels in hair predicted the progression of carotidatherosclerosis in a longitudinal study.31 Toenail mercury,however, did not predict the incidence of coronary heart diseasein a nested case–control study in U.S. health professionalsreported elsewhere in this issue of the Journal.32
Some limitations also need to be considered in the interpretationof our findings. Our analyses were based on single measurementsof mercury and DHA, and they are subject to random measurementerror. In addition, the levels of mercury or DHA were low inmany study participants, thus increasing the likelihood of analyticalerror. It is likely that the results of our analyses underestimatethe associations of both mercury and DHA levels with myocardialinfarction.
Another potential limitation of our study is that the participationrate was higher for patients than for controls. Although thisraises the possibility of selection bias, the association ofmercury levels with myocardial infarction was higher in centerswith higher participation rates, making selection bias an unlikelyexplanation of our results. Furthermore, because both mercuryand DHA are derived primarily from fish in the diet, selectionbias would be expected to influence associations of the levelsof both of these substances with myocardial infarction in thesame direction, not in opposite directions.
We did not have information on the sources of mercury or DHAor on the amount and type of fish consumed by the study participants.However, the high mercury levels in the two Spanish centersare consistent with the high consumption of fish in that country33and the high levels of mercury in fish caught in the Mediterranean34,35and consumed in those cities. The correlation between mercuryand DHA suggests that fish is probably the main source of mercuryin toenails in our populations, although other sources of exposureare possible. Finally, our patient population was restrictedto patients with myocardial infarction who survived until hospitalization.The observed associations thus cannot be generalized to patientswith acute cardiac events who die before hospitalization.
Fish intake is currently recommended to reduce the risk of cardiovasculardiseases36 and as part of a Mediterranean-type diet.37 However,the findings of epidemiologic studies of fish intake or fish-oillevels and coronary heart disease are contradictory, rangingfrom clearly inverse associations38,39,40 to virtually nullassociations17,41,42,43,44,45 and to positive associations.6Protective effects of fatty fish9 and fish-oil supplements10have been found in two secondary-prevention trials. In bothtrials, the protection was largely limited to fatal coronaryevents, whereas we found an inverse association between DHAlevels and nonfatal myocardial infarction. It is possible that,although the antiarrhythmic effects of fish oils may prevailin the prevention of recurrent events in patients who have hada myocardial infarction or in the prevention of sudden deathfrom cardiac causes,46,47 the antiaggregant and other antiatherogenicproperties of fish oils may also have a substantial preventiveeffect.
The risk of cardiovascular disease in a population may dependon the balance between n–3 fatty acids and methylmercuryin the fish consumed. Exposure to methylmercury is already aconcern in specific high-risk groups; the Food and Drug Administrationhas advised pregnant women and women who may become pregnantnot to eat swordfish, king mackerel, tilefish, shark, or fishfrom locally contaminated areas.48 Our results raise the possibilitythat this advice should be extended to the general adult population.However, our findings do not imply that people should stop eatingfish. Our mercury-adjusted analysis is consistent with a protectiveeffect of dietary fish, provided it is not heavily contaminated.
The Heavy Metals and Myocardial Infarction Project was supportedby a BIOMED-2 Concerted Action from the European Commission(research contract BMH4-CT98-3565) and was an ancillary projectto the EURAMIC Study. The national studies were financed bygrants from the British Heart Foundation, the Dutch Ministryof Health, the Spanish Fondo de Investigaciones Sanitarias,the German Federal Health Office, the Norwegian Research Council,the Russian Ministry of Science, the Swiss National ScienceFoundation, the Yrjö Jahnsson Foundation, and the IsraelScience Foundation.
Presented in part at the 42nd Annual Conference on CardiovascularDisease Epidemiology and Prevention of the American Heart Association,Honolulu, April 23–26, 2002.
We are indebted to the members of the EURAMIC Study Group formaking available the original data from the myocardial infarctionpart of their study. In addition to several of the authors,other members of the EURAMIC Study Group were Lenore Arab (ProjectManagement Group), Ramón Gálvez-Vargas (ProjectLeader), Jussi K. Huttunen (Project Management Group), AlwineF.M. Kardinaal (Project Management Group, Project Leader), BlaiseC. Martin (Project Leader), Vladimir P. Mazaev (Project Leader),J.J. Ringstad (Project Leader), and Michael Thamm (Project Leader).
* Other investigators are listed in the Appendix.
Source Information
From the Department of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore (E.G.); the Department of Epidemiology and Biostatistics, National School of Public Health, Institute of Health Carlos III, Madrid (E.G., M.I.S.-G., J.M.M.-M.); the Service of Preventive Medicine, Hospital 12 de Octubre, Madrid (M.I.S.-G.); the Division of Human Nutrition and Epidemiology, University of Wageningen, Wageningen, the Netherlands (P.V., F.J.K.); the Interfaculty Reactor Institute, Delft University of Technology, Delft, the Netherlands (P.B.); the Department of Health and Functional Capacity, National Public Health Institute, Helsinki, Finland (A.A.); the Department of Preventive Medicine, University of Málaga, Málaga, Spain (J.G.-A.); the Epidemiology Unit, Department of Social Medicine, Hadassah Medical Organization and Hebrew University–Hadassah School of Public Health and Community Medicine, Jerusalem, Israel (J.D.K.); the Cardiovascular Research Unit, University of Edinburgh, Edinburgh, United Kingdom, and the Department of Medical Physiology, University of Tromsø, Tromsø, Norway (R.A.R.); and the Department of Preventive Medicine, Universidad Autónoma de Madrid, Madrid (J.M.M.-M.)
Address reprint requests to Dr. Guallar at the Welch Center for Prevention, Epidemiology, and Clinical Research, 2024 E. Monument St., Suite 2-639, Baltimore, MD 21205-2223, or at eguallar{at}jhsph.edu.
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Appendix
Other investigators of the Heavy Metals and Myocardial InfarctionProject were Lydia Gorgojo, Institute of Health Carlos III,Madrid; Alwine F.M. Kardinaal, TNO Nutrition and Food Research,Zeist, the Netherlands; Jussi K. Huttunen, National Public HealthInstitute, Helsinki, Finland; Joaquín Fernández-Crehuet,Universidad de Málaga, Málaga, Spain; JoséF. Guillén, Universidad de Granada, Granada, Spain; MichaelThamm, Robert Koch Institute, Berlin, Germany; Blaise C. Martin,Zurich University, Zurich, Switzerland; Jetmund Ringstad, ØstfoldCentral Hospital, Fredrikstad, Norway; and Vladimir Mazaev,Russian Ministry of Health, Moscow, Russia.
Mercury and the Risk of Myocardial Infarction
Plante M., Babo S., Mutter J., Naumann J., Buettner C., Guallar E., Riemersma R. A., Kok F. J., Yoshizawa K., Rimm E. B., Willett W. C., Bolger P. M., Schwetz B.
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N Engl J Med 2003;
348:2151-2154, May 22, 2003.
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