Background Elevated plasma homocysteine levels are a risk factorfor coronary heart disease, but the prognostic value of homocysteinelevels in patients with established coronary artery diseasehas not been defined.
Methods We prospectively investigated the relation between plasmatotal homocysteine levels and mortality among 587 patients withangiographically confirmed coronary artery disease. At the timeof angiography in 1991 or 1992, risk factors for coronary disease,including homocysteine levels, were evaluated. The majorityof the patients subsequently underwent coronary-artery bypassgrafting (318 patients) or percutaneous transluminal coronaryangioplasty (120 patients); the remaining 149 were treated medically.
Results After a median follow-up of 4.6 years, 64 patients (10.9percent) had died. We found a strong, graded relation betweenplasma homocysteine levels and overall mortality. After fouryears, 3.8 percent of patients with homocysteine levels below9 µmol per liter had died, as compared with 24.7 percentof those with homocysteine levels of 15 µmol per literor higher. Homocysteine levels were only weakly related to theextent of coronary artery disease but were strongly relatedto the history with respect to myocardial infarction, the leftventricular ejection fraction, and the serum creatinine level.The relation of homocysteine levels to mortality remained strongafter adjustment for these and other potential confounders.In an analysis in which the patients with homocysteine levelsbelow 9 µmol per liter were used as the reference group,the mortality ratios were 1.9 for patients with homocysteinelevels of 9.0 to 14.9 µmol per liter, 2.8 for those withlevels of 15.0 to 19.9 µmol per liter, and 4.5 for thosewith levels of 20.0 µmol per liter or higher (P for trend= 0.02). When death due to cardiovascular disease (which occurredin 50 patients) was used as the end point in the analysis, therelation between homocysteine levels and mortality was slightlystrengthened.
Conclusions Plasma total homocysteine levels are a strong predictorof mortality in patients with angiographically confirmed coronaryartery disease.
Homocystinuria refers to a group of rare inborn errors of metabolismresulting in high levels of circulating homocysteine (>100µmol per liter) and urinary homocysteine. A characteristicfeature in patients with this condition is premature vasculardisease. If homocystinuria is untreated, about 50 percent ofpatients have thromboembolic events, and mortality is about20 percent before the age of 30 years.1 Observations in patientswith homocystinuria2,3,4 led to the idea that homocysteine maybe involved in the pathogenesis of arteriosclerosis5 and prompteda large number of epidemiologic studies of the relation betweenmoderately elevated homocysteine levels and vascular disease.
More than 75 clinical and epidemiologic studies have shown arelation between total homocysteine levels and coronary arterydisease, peripheral artery disease, stroke, or venous thrombosis.6,7,8,9,10The strongest evidence stems from prospective, nested case–controlstudies11,12,13,14,15; all but one11 found a relation betweentotal homocysteine levels and the frequency of vascular disease.
The prevailing view of the pathogenesis of coronary heart diseaseinvolves a slow progression of coronary atherosclerosis, followedby unstable angina, myocardial infarction, or sudden death.The acute event is frequently due to rupture or erosion of anatherosclerotic plaque with associated thrombus formation.16There is increasing evidence that homocysteine may affect thecoagulation system and the resistance of the endothelium tothrombosis17 and that it may interfere with the vasodilatorand antithrombotic functions of nitric oxide.18 Notably, thevascular complications reported in patients with homocystinuriaare related to thrombosis rather than to atherosclerosis,1,19and a relation between total homocysteine levels and the incidenceof thrombotic events has recently been reported in patientswith systemic lupus erythematosus.20 Previous investigationsof total homocysteine levels have not focused on acute eventsor mortality among patients with established coronary arterydisease.
In 1991 and 1992, we measured plasma total homocysteine in consecutivepatients who underwent coronary angiography for suspected ischemicheart disease. Cross-sectional analysis showed that the totalhomocysteine level was weakly related to the extent of coronaryartery disease but strongly related to the history with respectto myocardial infarction. We therefore assessed the relationbetween total homocysteine levels and mortality in the cohortfive years after coronary angiography.
Methods
Study Population
Between February 1991 and June 1992, we studied 802 consecutiveadult patients of both sexes who underwent diagnostic coronaryangiography at the Cardiology Department of Haukeland UniversityHospital in Bergen, Norway. For patients who were admitted forrecatheterization during that period, only the first study wasconsidered. In the present study, we excluded 139 patients whowere examined for reasons other than suspected ischemic heartdisease and 25 patients who had previously been treated withpercutaneous transluminal coronary angioplasty (PTCA) or whohad a prior myocardial infarction but a normal coronary angiogram.These exclusions did not affect the overall results. Among theremaining 638 patients, coronary artery disease was diagnosedin 587; the other 51 were classified as free of coronary arterydisease and were therefore excluded from the study cohort.
Informed consent was obtained from all the patients. All completeda one-page questionnaire that provided information about anyhistory of angina pectoris, hypertension, diabetes mellitus,and previous myocardial infarction. We also recorded any familyhistory of premature coronary heart disease (documented coronaryheart disease in at least one first-degree relative before theage of 55 years for men or 60 years for women), noncardiovasculardiseases, use of medications, adherence to a lipid-loweringdiet, and smoking habits.
The subjects were classified as current smokers, former smokers,or nonsmokers. Current smokers, including those who had stoppedless than one month before angiography, were divided into threegroups according to how many cigarettes they smoked per day:1 to 9, 10 to 19, or >20. The information from the questionnairewas checked against the patients' medical records; in all caseswith discrepancies or missing information, the patients weretelephoned by the primary investigator for clarification.
Classification of Previous Episodes of Vascular Disease
Cerebrovascular disease was defined as a history of transientischemic attacks (in 10 patients), unspecified stroke (7), thromboticstroke (6) or hemorrhagic stroke (1) verified by computed tomography,carotid-artery stenosis verified by Doppler echocardiography(4) or surgically treated (3), or the finding of a strong bruitover a carotid artery (6). A diagnosis of peripheral atheroscleroticdisease was given to patients with typical symptoms and clinicalsigns (63) and to those who had undergone surgery for this disorder(16). The diagnosis of previous myocardial infarction (in 337patients) was based on the medical history and records or onthe finding of typical sequelae of infarction on ventricularangiography.
Angiographic Evidence of Coronary Artery Disease
Angiograms were assessed by cardiologists who were unaware ofthe patients' risk-factor profiles, and coronary stenoses wereconfirmed in orthogonal views. Coronary artery disease was definedas a stenosis of at least 50 percent of the vessel diameterin any of the main coronary arteries (the left main coronaryartery or the left anterior descending coronary artery withits major diagonal branches, the right coronary artery, or thecircumflex coronary artery with its major marginal branch).Depending on dominance, the descending or posterior descendingcoronary artery was included as part of the right coronary arteryor the circumflex coronary artery. The extent of coronary arterydisease was scored as 0 (minimal or no disease), 1 (single-vesseldisease), 2 (two-vessel disease), or 3 (three-vessel disease),according to the number of main vessels with stenosis. Stenosisof a left main-stem artery without stenosis of the right coronaryartery was classified as two-vessel disease. The left ventricularejection fraction was assessed by ventriculography.
Follow-Up and Causes of Death
From the National Population Register, we obtained the datesof death for all patients who died between the time of angiographyin 1991 or 1992 and April 30, 1996. Causes of death were obtainedfrom death certificates kept at Statistics Norway. Fifty ofthe 64 deaths (78 percent) were classified as due to cardiovascularcauses. These included acute myocardial infarction (26 deaths);coronary atherosclerosis (15 deaths; 10 of these deaths werealso coded as sudden death from cardiac causes or as due tofatal arrhythmia, 2 as due to congestive heart failure, 1 toasphyxia, and 1 to rejection of a heart transplant; 1 was notfurther subclassified); cerebrovascular events (6); rupturedabdominal aneurysm (1); and aortic stenosis (1). One patientwhose death was listed in the register only as sudden deathwas also included among the 50 cases classified as due to cardiovasculardisease. The 14 deaths due to noncardiovascular causes weredue to cancer ( 10), diabetes mellitus (1), an accident ( 1),renal failure (1), and ulcerative colitis (1).
Biochemical Measurements
After the patients had fasted overnight, samples of venous bloodwere drawn into tubes containing EDTA. Plasma was separatedfrom blood cells by immediate centrifugation. Plasma total homocysteine,which includes the sum of protein-bound and free homocysteine,was measured by high-performance liquid chromatography withfluorescence detection.21,22
Serum total cholesterol and triglycerides were measured by aTechnicon Chem 1 assay (Technicon Instruments, Tarrytown, N.Y.),and high-density lipoprotein cholesterol was measured in thesupernatant after precipitation of apolipoprotein B–containinglipoproteins with heparin–manganese chloride. Low-densitylipoprotein cholesterol was calculated by the formula of Friedewaldet al.23 for patients with serum triglyceride concentrationsbelow 354 mg per deciliter (4.0 mmol per liter). Serum apolipoproteinA-I and apolipoprotein B were assayed by laser nephelometrywith standards and antiserum from Behring Diagnostics (Behringwerke,Marburg, Germany). Serum Lp(a) lipoprotein was assayed witha radioimmunoassay (Pharmacia, Uppsala, Sweden). These sevenindexes are referred to as lipid-related factors.
The serum folate concentration was assayed with use of the Quantaphasefolate radioassay (Bio-Rad, Hercules, Calif.). Serum vitaminB12 was measured with a microparticle enzyme intrinsic-factorassay run on an IMx system (Abbott, Abbott Park, Ill.).
The coefficients of variation within and between days for theassays were 5 percent or less, except for the Lp(a) lipoproteinassay (3 to 6 percent) and the apolipoprotein B assay (6 to10 percent).
Statistical Analysis
Because the distributions of values for total homocysteine,Lp(a) lipoprotein, triglycerides, vitamin B12, folate, and creatininewere markedly skewed, these variables were logarithmically transformed,and geometric means are presented. In subgroups of patients,mean levels were compared by analysis of variance and adjustedmeans by analysis of covariance. Survival was studied with Kaplan–Meiermethods and Cox regression. Adjusted survival curves were estimatedin a model stratified according to the total homocysteine levelwith use of S-PLUS software.24 The log-rank test and score testswere used throughout, and tests for linear trend were used toassess graded associations. Median follow-up time was calculatedby the reverse Kaplan–Meier method.25 In all regressionanalyses, the covariates were represented by indicator variablesto allow for nonlinear dose–response relations. The dose–responserelation between the total homocysteine level and mortalitywas also estimated with generalized additive logistic regression,26as implemented in S-PLUS. This method generates a graphic representationof the relation between the total homocysteine level and mortalityon a logit scale, after adjustment for other covariates.
The analyses were performed with BMDP27 or S-PLUS24 software.Two-sided P values below 0.05 were considered to indicate statisticalsignificance.
Results
Characteristics of the Patients
The median age of the 478 men and 109 women with coronary arterydisease was 62 years; 15 percent were younger than 50 years,and an equal proportion were 70 years of age or older. A totalof 128 patients had unstable angina, 337 had had a previousmyocardial infarction, and 64 had previously undergone coronary-arterybypass grafting. Diabetes mellitus had been diagnosed in 44patients, 159 were being treated for hypertension, 156 weresmokers, and 284 were former smokers. Aspirin was used by 45percent of the patients, a beta-blocker by 73 percent, a calcium-channelblocker by 44 percent, an angiotensin-converting–enzymeinhibitor by 9 percent, and a lipid-lowering drug by 6 percent.
Angiography revealed that 94 patients had single-vessel disease,172 had two-vessel disease, and 321 had three-vessel disease.Seventy-four patients had a left ventricular ejection fractionbelow 50 percent. After the angiographic study in 1991 or 1992,120 patients were referred for PTCA and 318 for coronary-arterybypass grafting; 72 patients had no indication for revascularizationtherapy, whereas 77 patients were not accepted for revascularizationtherapy because of diffuse peripheral coronary artery disease(65 patients), a high risk entailed by the procedure (8), orserious noncardiac disease (4).
Predictors of Plasma Total Homocysteine Levels
The mean total homocysteine level was 11.4 µmol per literin men and 10.5 µmol per liter in women (P = 0.02), andit increased by 1.3 µmol per liter, on average, with eachadditional 20 years of age (P< 0.001). The mean level was1.0 µmol per liter higher in patients with a previousmyocardial infarction than in those without such a history (P<0.001),1.2 µmol per liter higher in patients with a left ventricularejection fraction below 50 percent than in those with highervalues (P = 0.01), 0.7 µmol per liter higher in patientsreceiving hypertensive therapy than in those not receiving suchtherapy (P = 0.03), and 0.4 µmol per liter higher in patientswith unstable angina than in those with stable symptoms (P =0.28). After adjustment for age and sex, the strongest predictorsof the total homocysteine level were the serum folate level(r = - 0.36, P<0.001), the serum creatinine level (r = 0.30,P<0.001), the serum uric acid level (r = 0.17, P<0.001),the serum vitamin B12 level (r = -0.15, P<0.001), and theleft ventricular ejection fraction (r = 0.13, P<0.001).
Plasma Total Homocysteine Levels and Overall Mortality
After a median follow-up of 4.6 years (range, 3.9 to 5.3), 53men (11.1 percent) and 11 women (10.1 percent) had died. Therewas a strong, graded dose–response relation between thetotal homocysteine level and overall mortality. At four years,Kaplan–Meier estimates of mortality were 3.8 percent forpatients with total homocysteine levels below 9 µmol perliter, 8.6 percent for those with levels of 9 to 14.9 µmolper liter, and 24.7 percent for those with levels of 15 µmolper liter or higher (P for trend <0.001). The clear, gradeddose–response relation was also evident in the Cox-adjustedsurvival plot (Figure 1).
Figure 1. Estimated Survival among Patients with Coronary Artery Disease, According to Plasma Total Homocysteine Levels.
The figure shows estimated survival for 55-year-old male former smokers with three-vessel disease, a left ventricular ejection fraction of 55 percent, a creatinine level of 1.5 mg per deciliter (130 µmol per liter), and a total cholesterol level of 241 mg per deciliter (6.24 mmol per liter) at four different total homocysteine levels. Survival curves have been estimated in a stratified Cox regression analysis.
Table 1 shows the results of the Cox regression analyses. Afteradjustment for sex and age, the strongest predictors of mortalitywere the left ventricular ejection fraction, the total homocysteinelevel, and the creatinine level. The inclusion of all thesefactors in the same model weakened the predictive power of each,but they all remained strong and significant. The total homocysteinelevel and the creatinine level each weakened the effect of theother on the prediction of mortality, whereas they had lesseffect on the relation between the left ventricular ejectionfraction and mortality. The left ventricular ejection fractionattenuated the relation of homocysteine levels to mortalitymore than it did the relation of creatinine levels to mortality.
Table 1. Mortality Ratios during a Median Follow-up of 4.6 Years among 587 Patients with Angiographically Confirmed Coronary Artery Disease in 1991 or 1992, According to Prognostic Variables.
When other potential confounders were included in the finalmultivariate model (Table 1), the homocysteine–mortalityrelation was somewhat further attenuated, in particular by theuse of aspirin and to a lesser degree by hypertensive therapy.Additional adjustment for prognostic variables such as presenceor absence of treatment with PTCA or coronary-artery bypassgrafting, use of medication, presence or absence of unstableangina, history with respect to myocardial infarction, and theuric acid level had minimal effect, and these variables werenot included in the final model.
The association between homocysteine levels and mortality wasalso studied in various subgroups. In these analyses, we comparedmortality among patients with total homocysteine levels of atleast 15 µmol per liter to that among patients with lowerlevels. Higher total homocysteine levels were associated witha significant increase in mortality among both sexes, in nonsmokers,in both older people (>65 years) and younger ones (<65years), in subjects with and those without a previous myocardialinfarction, in those with a reduced ejection fraction (<50percent) and those with a normal ejection fraction, in thosewith normal creatinine levels (<1.4 mg per deciliter [<120µmol per liter]), and in those referred for subsequenttreatment with coronary-artery bypass grafting and those treatedconservatively. A higher total homocysteine level was also associatedwith increased mortality among current smokers and among patientswith elevated creatinine levels (>1.4 mg per deciliter),but these relations were not statistically significant.
When we used generalized additive logistic regression to estimatethe adjusted dose–response relation between total homocysteinelevels and mortality (Figure 2), we found that the relationwas nearly linear from a total homocysteine level below 5 µmolper liter to one above 20 µmol per liter, but with a steeperslope above 15 µmol per liter. On the basis of this dose–responserelation, we estimated that the mortality ratio for an increaseof 5 µmol per liter in the total homocysteine level was1.6 between 10 and 15 µmol per liter and 2.5 between 15and 20 µmol per liter.
Figure 2. Dose–Response Relation between Plasma Total Homocysteine Levels and Mortality.
The values have been adjusted for age, sex, left ventricular ejection fraction, creatinine level, total cholesterol level, and the extent of coronary artery disease with the use of generalized additive logistic regression. The relative mortality was approximated by the odds ratio. The solid line indicates the estimated dose–response curve, and the shaded area the 95 percent confidence interval.
The lipid-related factors showed either no relation or a muchweaker relation to mortality than the total homocysteine level.Among these measurements, apolipoprotein A-I showed the strongestrelation to mortality, but with borderline significance. Wefound only a weak, nonsignificant inverse relation between theserum folate level and the risk of death; this association disappearedafter we adjusted for the plasma total homocysteine level. Theserum concentration of vitamin B12 was not related to mortality,and adjustment for the serum folate or vitamin B12 level hadno influence on the relation between total homocysteine andmortality.
Plasma Total Homocysteine Levels and Mortality from Cardiovascular Causes
When the end point analyzed was the deaths classified as dueto cardiovascular causes (50 deaths, or 78 percent of the total),the relation between homocysteine and mortality was slightlystrengthened. With a total homocysteine level below 9 µmolper liter as the reference category and with adjustment forage and sex, the mortality ratio was 3.3 for patients with totalhomocysteine levels of 9.0 to 14.9 µmol per liter, 6.3for those with levels of 15.0 to 19.9 µmol per liter,and 9.9 for those with levels of 20.0 µmol per liter orhigher (P for trend <0.001). With further adjustment forthe left ventricular ejection fraction, creatinine level, totalcholesterol level, and the number of coronary arteries withstenosis (as in the second model in Table 1), the correspondingmortality ratios were 2.3, 2.5, and 7.8 (P for trend = 0.01).
Predictors of Coronary Artery Disease and Previous Myocardial Infarction
We also studied predictors of coronary artery disease measuredat base line in 1991 or 1992. In these analyses, we includedthe 51 patients without clinically significant coronary-arterystenosis. The extent of coronary artery disease (graded as nocoronary artery disease or single-vessel, two-vessel, or three-vesseldisease) was only weakly related to the total homocysteine levelbut was strongly associated with the lipid-related factors.Lp(a) lipoprotein was the strongest predictor in both sexes(Table 2). In contrast, having had a previous myocardial infarctionwas not associated with the lipid-related blood values but wasstrongly associated with total homocysteine (P< 0.001). Serumfolate and vitamin B12 were related neither to the extent ofcoronary artery disease nor to the history with respect to myocardialinfarction.
Table 2. Biochemical Measurements According to the Extent of Coronary Artery Disease among 142 Women and 496 Men Who Underwent Cardiac Catheterization for Suspected Ischemic Heart Disease in 1991 or 1992.
Discussion
We found a strong, graded association between the plasma totalhomocysteine level and overall mortality in patients with angiographicallyconfirmed coronary artery disease. The relation between thetotal homocysteine level and mortality was already apparentwithin a few months of the base-line coronary angiogram. Inline with previous prospective studies of patients with coronaryheart disease,28 close to 80 percent of all deaths in our studywere classified as due to cardiovascular disease, on the basisof the information on the death certificate. The number of eventswas too small to permit detailed, cause-specific analyses, butthe relation between total homocysteine and mortality was strengthenedwhen death due to cardiovascular causes was used as the endpoint.
The dose–response relation was observed within the rangeof total homocysteine values from about 5 µmol per literto more than 20 µmol per liter. Although the relationwith mortality was strongest for total homocysteine levels above15 µmol per liter, the association was also substantialfor lower levels. Notably, we calculated an adjusted mortalityratio of 1.6 for patients with total homocysteine levels of15 µmol per liter as compared with those with values of10 µmol per liter. A meta-analysis of data from previousobservational studies of patients with coronary artery diseasedemonstrated a similar increase in risk for each increase of5 µmol per liter in the total homocysteine level.7 A gradedrelation between total homocysteine levels and cardiovascularevents has been demonstrated in some, but not all, previousstudies.11,12,13,14,15,29
In comparison with the strong relation between total homocysteinelevels and either mortality or previous myocardial infarction,total homocysteine levels were associated only weakly with thenumber of coronary arteries with stenosis. In contrast, thelipid-related factors were strongly related to the extent ofcoronary artery disease, but only weakly to mortality or previousinfarction. These observations suggest that elevated total homocysteinevalues are strongly related to the risk of acute events leadingto death. However, risk factors for cardiovascular disease arenot exclusively atherogenic or thrombogenic,30,31 and previousstudies have shown a direct relation between total homocysteinelevels and the number of coronary vessels with stenosis32,33,34,35or carotid-artery stenosis.36,37
A critical question is whether the relation of homocysteineand mortality is due to confounding by an association of totalhomocysteine levels with other strong predictors of mortality,such as the serum creatinine level, left ventricular ejectionfraction, or history with respect to myocardial infarction.Adjustment for these factors weakened the predictive power oftotal homocysteine levels somewhat. However, impaired renalfunction increases total homocysteine levels,38 and high totalhomocysteine levels are a risk factor for myocardial infarction,12,13,29which, in turn, is the primary determinant of the left ventricularejection fraction in patients with coronary disease. Thus, ifhigh total homocysteine levels and these strong prognostic factorsshare a common causal pathway, adjustment for any of these factorsmay cause the true relation between the total homocysteine leveland mortality to be underestimated. In fact, total homocysteinehas been related to mortality due to cardiovascular diseaseand to total mortality in patients with end-stage renal disease.38
To evaluate further the possibility of confounding, patientswere divided into subgroups according to the presence or absenceof the other strong predictors of a higher mortality rate —elevated serum creatinine levels, previous myocardial infarction,and a reduced left ventricular ejection fraction. The relationof total homocysteine to mortality was strong in all these subgroups,further suggesting that the homocysteine–mortality relationis not explained completely by these factors.
Adjustment for several other risk factors for cardiovasculardisease that have previously been reported to be related tototal homocysteine levels33,39,40 — including smokingstatus, total cholesterol levels, other lipid-related factors,and the presence or absence of hypertension or diabetes mellitus— only weakly attenuated the strong relation of homocysteineand mortality.
In conclusion, we found that the plasma total homocysteine levelwas the strongest modifiable predictor of overall mortalityand mortality due to cardiovascular causes among patients withangiographically confirmed coronary artery disease. This prospectivestudy does not prove a causal relation between total homocysteineand mortality, but our results should serve as an additionalstrong incentive to the initiation of intervention trials withhomocysteine-lowering therapy.
Supported by the Norwegian Council on Cardiovascular Diseasesand the Norwegian Research Council.
We are indebted to Elfrid Blomdal, Alf Aksland, and the staffat the Laboratory of Clinical Biochemistry, Haukeland UniversityHospital, for their valuable assistance in this study; to HåkonK. Gjessing for statistical advice; and to Finn Gjertsen andthe staff at Statistics Norway for expediting the processingof death certificates for this study.
Source Information
From the Division for Medical Statistics, Department of Public Health and Primary Health Care (O.N., S.E.V.), the Department of Pharmacology (H.R., P.M.U.), and the Division of Biochemistry, Department of Clinical Biology (M.F.), University of Bergen; and the Department of Heart Disease, Haukeland University Hospital (O.N., J.E.N.) — all in Bergen, Norway.
Address reprint requests to Dr. Nygård at the Department of Heart Disease, Haukeland University Hospital, 5021 Bergen, Norway.
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