ESR, Cornary Ateroschlerosis, And Cardiac Mortality

Erythrocyte sedimentation rate, coronary atherosclerosis, and cardiac mortality

Andrea Natali , Antonio L'Abbate , Ele Ferrannini

DOI: http://dx.doi.org/10.1016/S0195-668X(02)00741-8 639-648 First published online: 1 April 2003

Article Figures & data Information Explore PDFAbstract

Aims To test whether the erythrocyte sedimentation rate (ESR) is related to the extension of coronary atherosclerosis (ATS) and predicts cardiac mortality.

Methods and results Hospital-based, retrospective observational (median follow up: 92 months) cohort study. In 1726 consecutive patients undergoing angiography, coronary ATS and subsequent mortality were related to ESR and to classical risk factors. Patients INCLUDEPICTURE "http://d1vzuwdl7rxiz0.cloudfront.net/sites/default/files/highwire/ehj/24/7/639/embed/tex-math-1.gif" \* MERGEFORMATINET

undergoing angiography for reasons different from ischemic heart disease (IHD), served as control. ESR was progressively higher in the presence of 1, 2, or 3-vessel disease. Age-and sex-adjusted ESR was positively related to ATS both in univariate analysis (, ) and in a multivariate model including principal risk factors (partial , ). Similar associations were observed in the control group. Over the follow-up period, 170 patients died of a cardiac cause. When male and female patients in their upper ESR quartile (>18 and >23mm/h, respectively) were compared with the remainder of the cohort, their age-and gender-adjusted odds ratio for cardiac mortality was 1.72 (, ). This result held true, in men, also when using a full set of risk factors in a Cox model.

Conclusions ESR is an independent correlate of coronary ATS and, in male patients with probable IHD, a predictor of cardiac death.

Erythrocyte sedimentation rate

Inflammation

Coronary atherosclerosis

Cardiac mortality

Risk factors

Ischemic heart disease

1 Introduction

Histopathologic studies have consistently shown that inflammatory cells not only participate in the initiating events leading to plaque formation(adesion of monocytes to activated endothelial cells, migration into subendothelial layers, and transformation into macrophages), but also affect the subsequent evolution of the lesion. Activated T lymphocytes are present in the lipid core of atherosclerotic lesions and, through the release of cytokines, stimulate macrophage migration andactivation, inhibit collagen synthesis, and induce neovascularization.1 Thus, various indices of systemic inflammation (white blood cell count, serum interleukin-6, fibrinogen, C-reactive protein, and albumin concentrations) have been reported to predict ischemic heart disease (IHD) development both in healthy subjects and in at-risk patients.2 Whether inflammation is a risk factor for IHDbecause it favours the occurrence of clinical events (e.g. through plaque destabilization and/or blood clotting) or because it heralds the presence of a more extensive coronary atherosclerosis (ATS), is unknown. Similarly, the notion that rheologic characteristics of blood contribute to the pathogenesis of IHD is gaining growing support. The major components of blood viscosity are the blood cell mass (i.e. the hematocrit), the intrinsic resistance of the plasma to flow (commonly measured by capillary viscometry), and red blood cell aggregability, which can be estimated through the erythrocyte sedimentation rate (ESR). A recent meta-analysis of population-based studies3 calculated that the IHD risk ratios of subjects in the top vs bottom tertile of the distribution of hematocrit, plasma viscosity, and ESR were 1.60, 1.57, and 1.33, respectively. Even higher risk ratios (1.81 for hematocrit and 2.60 for plasma viscosity) were found in patients with preexisting cardiovascular disease, whereas no data are available on the prognostic value of ESR in these patients. In general, in comparison with the other indices of blood viscosity (19 studies of haematocrit and six of plasma viscosity,3) ESR has been somewhat neglected, with two large4,5 and three very small68 prospective studies published in the last three decades. One reason might be that the ESR can only be measured on fresh bloodsamples, and is confounded by gender, age,hematocrit, as well as the presence of many acute or chronic illnesses. On the other hand, the ESR measurement by the Westergren method is standardized, accurate, universally available, and cheap. Furthermore, when red blood cell physical characteristics are taken into account by adjusting for hematocrit, ESR largely reflects the plasma concentration of acute phase response proteins resulting in a compound index of both viscosityand inflammation. Despite the rationale, relatively scarce information is available on theassociation of ESR with the anatomical status ofthe coronary circulation. This prompted us to carry out the present retrospective analysis of patients undergoing coronary angiography for the clinical workup of ischemia, in whom we tested whether ESR was related to the severity of coronary ATS and whether it predicted subsequent cardiac death.

2 Methods

2.1 Patients

We analyzed data from 2263 consecutive patients undergoing coronary angiography over the decade 19831992. Most of the patients underwent coronary angiography as part of the clinical workup for IHD; of these, 228 (12%) had previously suffered a myocardial infarction (PMI), 45 (2%) were admitted with an acute myocardial infarction (AMI), and 1679 (86%) presented with either resting or effort angina. ESR data were available for 1726 of these patients (88%); the clinical characteristics of this group (Table 1) were superimposable on those of the whole population ( for all variables by MannWhitney U test, data not shown). In the remaining 311 subjects, coronary angiography was performed as part of the clinical evaluation for valvular disease , dilated or hypertrophic cardiomyopathy , arrhythmia , or other . ESR was available for 86% of these patients.

Enlarge tableTable 1

Clinical characteristics of the patients

MeanSDRange

n1726

M/F1380/346

Age (years)55101784

BMI (kg m2)26.43.214.939.5

Familial IHD (score)1.12.1022

Alcohol consumption (g/week)16618201893

Diabetes (%)12.2

Smoking habits (n/ex/y; in %)24/53/23

Cigarette consumption (pack-years)a32(32)0.1225

Systolic BP (mmHg)1281490188

Diastolic BP (mmHg)81859110

Heart rate (bpm)6484298

Hematocrit (%)40.13.926.056.1

Serum total cholesterol (mmol/l)5.571.322.5921.76

Serum triglycerides (mmol/l)b1.66(1.02)0.4025.4

a Geometric mean and (interquartile range) for the 1278 subjects who were past- or current-smokers.

b Geometric mean and (interquartile range).

IHD=ischemic heart disease; BMI=body mass index; BP=arterial blood pressure; n/ex/y=never smokers/past-smokers/ current-smokers.

2.2 Database

Since 1983, a standard record was completedfor each patient undergoing angiography by the cardiologist in charge. Before permanent storage, each record was checked by a computer expert and senior cardiologist, for logical or clinical inconsistencies as well as uniformity of entry criteria.;comptd;;center;stack;;;;;6;;;;;width> ;comptd;;center;stack;;;;;6;;;;;width> Each record consisted of the following three blocks of information: (a) Demographics: Gender, age, height, weight; (b) Clinical data: PMI or AMI, resting, effort, and unstable angina all diagnosedaccording to clinical criteria; (c) Angiographic data: Any stenosis (graded as 50, 75, 90, and 100%) along each coronary artery (main stem (MS), left anterior descending artery (LAD), circumflex artery (CX), and right coronary artery (RCA)) as well as secondary branches was described. A coronaryvessel was considered to have a clinicallysignificant obstruction if it was stenosed by at least 50% with respect to the prestenotic segment; when multiple stenoses were present on the same main vessel, the grade of the narrowest one was considered. These descriptions constituted the basis for the diagnosis of 1-, 2-, or 3-vessel disease.From the description of the angiograms, a score of cumulative coronary ATS (expressed in arbitrary units9) was calculated as the sum of all detectable percent narrowings in the entire coronarytree (including multiple stenoses along thesame vessel; irregularities were considered asa single 40% stenosis). Formal validation ofthe visual grading system against quantitative angiographycomputer-assisted edge evaluation (Kontron M14, Kontron Image Analysis Division,Munich, Germany)was carried out in a subset of stenoses randomly selected from the present data collection in a blind fashion. When the percent reduction of the stenotic segment relative to the pre-stenotic segment was calculated as the ratio of the two areas, the values coded as irregularities, 50, 75, and 90% by visual grading corresponded to 535, 743, 801, 831% narrowing, respectively, on quantitative angiography; and (d) Follow-up data: Information concerning death was collected yearly up to 15 years after discharge from the following sources: outpatient visits, telephone interviews (with the patients, close relatives, or the referring physician), questionnaires sent to all patients, and death certificates. The data were interpreted by the cardiologist in charge of the database, who classified the events as: no event, cardiac death (which included sudden death, acute left ventricular dysfunction, fatal myocardialinfarction, and death during or immediately after coronary bypass surgery), and noncardiac death (which included cancer, accident, stroke, acute pulmonary disease, etc.).

Download figure Open in new tab Download powerpointFig. 1

ESR according to the number of vessel with clinically significant (50%) coronary stenosis (top) and to the extent of coronary ATS units (bottom) in 1380 men and 346 women. Each point plots the geometric mean.


ATS by gender and quartile of ESR in diabetic and nondiabetic patients (top) and in patients with normal or high (>5.2mmol/l) serum total cholesterol concentrations (bottom). Bars are geometric means of ATS.

2.3 Clinical chart review

The original database was integrated with additional information collected retrospectively through detailed review of the individual clinical charts, as follows: (a) Familial IHD was expressed as a score derived from the number of first-degree relatives affected (1 for a parent, for each affected of siblings). Second-degree relatives were also included (with a score of 0.1). Theses values were multiplied by 5, if the subject was affected before 60 years of age (for men, 70 for women); (b) Diabetes mellitus was defined bythe presence of antidiabetic treatment or if two measurements of fasting plasma glucose were greater than 7.0mmol/l.10 Hypertension wasdefined by current antihypertensive treatment, or blood pressure values (as the average morning reading) 140/90mmHg11 or a documented history of high blood pressure; (c) Patients were classified as current-smokers, past-smokers, or never-smokers. Cigarette consumption was also estimated, and expressed in pack-years (when not specified, age 17 was assumed as the beginning). Current alcohol consumption was expressed in grams per week based on the average weekly consumption of wine, beer, and spirits. An average ethanol content of 11g for each wine serving (120ml), 13g for each beer serving (250ml), and 15g for each spirit serving (40ml) wasassumed; (d) From the routine chemistry done on fasting blood on admission, the following data were also taken: plasma creatinine and uric acid, serum total cholesterol, and triglycerides, leukocyte count, ESR, and hematocrit.

2.4 Methods

Cardiac catheterization was performed by the Seldinger technique. During ventricular and coronary angiography, at least three different views were recorded for each patient on a 35-mm film. Blood samples were analysed by the samelaboratory. Plasma glucose, cholesterol, and triglyceride concentrations were measured by routine enzymatic methods; hematocrit was measuredby microultracentrifugation. ESR was measured by the modified Westergren method (automated ona VES-Matic); in our laboratory, upper limits of normal are 12 and 17mm/h, in adult men and women, respectively and the coeficient of variation of duplicates is 9%.

2.5 Statistical analysis

Dataare presented as meanSD. ESR and serum triglyceride values were log-transformed for statistical analysis and mean data given as geometric mean and interquartile range. Forcigarette consumption and the ATS score, the transformation was used in statistical analysis. Between-group mean differences were tested by the MannWhitney U test (KruskallWallis test for three or more groups) or the 2test, for continuous variables and proportions,respectively. When comparing mean group values stratified by another ordinal variable, two-way analysis of variance (ANOVA) was used. Simple and multiple regression analyses were carried outby standard methods. Survival was analyzed by generating KaplanMeier cumulative hazard plots for groups, which were then compared by the logrank (MantelCox) test. Odds ratios (OR)and their 95% confidence intervals (CI) werecalculated using Cox regression models.


Multiple regression analysis

ATSLADCXRCATotal

Intercept3.00 (4.03)3.21 (2.71)3.51 (3.53)2.94(5.13)

Male sex0.32 (0.30)0.25 (0.26)0.30 (0.26)0.39(0.33)

Age0.23 (0.19)0.19 (0.21)0.19 (0.18)0.23(0.24)

Diabetes0.11 (0.17)0.16 (0.21)0.13 (0.14)0.14(0.17)

Serum cholesterol0.13 (ns)0.13 (ns)0.16 (0.10)0.16 (0.12)

Smoking0.05 (ns)0.12 (ns)0.12 (ns)0.13 (ns)

ESR0.09 (0.30)0.07 (0.16)0.10 (0.20)0.12 (0.24)

Alcohol consumptionns (0.10)0.08 (0.12)0.07 (0.12)0.06(0.12)

Hypertension0.05 (ns)ns (ns)ns (ns)0.05 (ns)

Explained variance (%)20 (29)17 (21)20 (25)2530 (29)

Entries are standardized coefficients, at a significance level less than 0.05, for the patients undergoing angiography for the clinical work-up of IHD and in the control group (in bracket); ns=not significant. LAD=left anterior descending coronary artery; CX=circumflex coronary artery; RCA=right coronary artery. ESR was entered as , smoking (pack-years) and coronary stenosis as .

3 Results

ESR was higher in women than in men (14 [15] vs 8 [10]mm/h, ); in either sex, it increased with age (by 2.4mm/h per decade, , in men; 4.7mm/h per decade, , in women), and decreasedwith increasing hematocrit (by 1.3mm/h per unit of hematocrit, , in men; 0.8mm/h per unit of hematocrit, , in women). In nonsmokers, ESR was significantly higher than in past- or current-smokers (16 vs 13 vs 12mm/h, ), whereas the hematocrit showed the reverse trend (38.4 vs 40.5 vs 40.8%, ); past-and current-smokers were more frequently men (93 and 88%, respectively), whereas women were more prevalent (57%) among never smokers. After adjusting for sex and hematocrit, ESR was not affected by smokinghabits. Of the 213 diabetic patients (155 men, 58 women), five had type 1 diabetes and 208 had type 2 diabetes. In the whole diabetic group, ESR was higher than in nondiabetic subjects, in men (10 [13] vs 8 [10]mm/h, ) as well as women (20 [17] vs 13 [15]mm/h, ). In the 689 patients with hypertension (535 men, 154 women), ESR was higher than in normotensive subjects, in men (9 [11] vs 8 [9]mm/h, ) and women (16 [16] vs 13 [15]mm/h, ). In univariate analysis, ESR was found to be positively related to body mass index, heart rate, serum total cholesterol, and smoking, and inversely related to alcohol consumption. In multivariate analysis, hematocrit, age,serum total cholesterol, heart rate, body massindex, diabetes, gender, and alcohol consumption (in that order) were independent predictors of ESR ( and for the model).

ESR was progressively higher in the presence of angiographically documented major narrowing (>50%) of 0, 1, 2, or 3 major coronary vessels( by two-way ANOVA), and was positively related to the ATS score in univariate analysis in both men (, ) and women (, ) (Fig. 1). The ATS score was higher in men than women (140 [280] vs 19 [271] units, ), in diabetic than nondiabetic patients (240 [280] vs. 82 [267] units, ), in hypertensive than normotensive patients (125 [300] vs 76 [285] units, ), and in past-smokers (139 [285] units) than in current or never-smokers (103 [240] and 36 [344] units, respectively, ). In univariateassociation, the ATS score was also higher with;comptd;;center;stack;;;;;6;;;;;width> increasing age, serum total cholesterol and triglyceride levels, and hematocrit. By stepwiseregression analysis, sex, age, serum cholesterol, presence of diabetes, cigarette consumption,alcohol consumption (negatively), hypertension (in that order) were all independently associated withthe ATS score, together accounting for 28% of its variability.


Cumulative hazard plot for all-cause and cardiac mortality in men (squares) and women (circle) in the top quartile (filled symbols) or in the lower three quartiles (empty symbols) of ESR distribution. These patients (1380 men and 346 women) underwent coronary angiography for the clinical work up of ischemic heart disease. The values refer to the logrank test.

When patients were stratified by sex and presence of diabetes, the independent associationbetween ESR and ATS was still statistically significant (by two-way ANOVA) in both men and women (Fig. 2). By defining hypercholesterolemia as a serum total cholesterol >5.2mmol/l, 999 patients (206 women) werehypercholesterolemic. Upon stratifying the cohort by sex and hypercholesterolemia, ATS was related to ESR in both men and women ( for the independent effect of ESR) (Fig. 2). To further test the independent association between ESR and ATS, a multivariate model was set up that included covariates common to both (age, diabetes, and serum cholesterol), as well as all variables that were univariately related to either ESR or ATS. The results (Table 2) show that coronary stenosisremained independently associated with ESR (for each of the three main coronary arteries andglobally). Furthermore, the model yielded similar standardized regression coefficients in the patients undergoing angiography for the clinical workup of IHD and in the control group. The latter had a better cardiovascular risk profile (with a higher prevalence of never smokers (39 vs 24%), lower serum cholesterol (4.981.19 vs 5.571.32mM) and triglycerides (1.58 [0.82] vs 1.67 [1.02]mM) concentrations, for all) and a much lower ATS score (5 [50] vs 94 [290] units, ). Nevertheless, the standardized coefficients indicate a similar, close association between ESR and coronary ATS compared to the IHD group.

Over a median follow-up period of 92 months (range 0191), 259 patients in the IHD group died; of these, 170 died of a documented cardiac cause. When the survival of the patients in the upper quartile of ESR distribution (>18 in men and >23mm/h in women) was compared with that of the remainder of the cohort, there was a significant increase in both total and cardiac mortality in men as well as women ( for both) (Fig. 3). The age-and gender-adjusted OR for cardiac death was 1.72 (, ).

When the full set of risk factors was used in a Cox model (also including the hematocrit), ESR values in the upper quartile still behaved as a negative prognostic index, particularly for cardiac mortality (Table 3). An ESR greater than 18 for men and 23mm/h for women was a predictive factor also, after adjusting for the presence of PMI and unstable angina (OR: 1.67, ). Fully adjusted cumulative hazard plots for men in the upper ESR quartile (>18mm/h) and for men with a PMI against the rest of the cohort are compared in Fig. 4;comptd;;center;stack;;;;;6;;;;;width> .


Mortality risk

All causespCardiac causesp

Sex (male)2.08 (1.323.29)0.0022.02 (1.173.50)0.01

Age (10 years)2.01 (1.722.36)15mm/h)1.30 (0.971.74)0.081.71 (1.202.43)0.003

Entries are OR and (95% CI) generated by the Cox multiple regression model.


Residual (following adjustment for age, diabetes, hypertension, alcohol consumption, smoking habits, hypercholesterolemia, and hematocrit) cumulative risk of cardiac death in men with an ESR>18 mm/h (filled symbols) or 18 mm/h (empty symbols). The lower panel shows the equivalent plot for men with and without previous myocardial infarction (PMI). These patients (1380 men) underwent coronary angiography for the clinical work up of ischemic heart disease. The value refer to the log-rank test.

4 Discussion

ESRwhich measures the tendency of red blood cells to aggregateis a time-honored, routine analysis mainly used to screen for the presence of hidden inflammation, and to help in the diagnosis and follow-up of chronic diseases. In our cohortof patients largely selected for the presence of symptoms or signs of IHD, ESR showed an interesting behavior. After adjusting for sex and hematocrit, ESR was directly associated not only with age, serum cholesterol, hypertension, heart rate, BMI, and diabetes, and inversely related to alcohol consumption i.e. with a set of variables that are also well known risk factors for IHD, but also with the extent of coronary ATS. Since the major determinants of ESR are the concentration of positively charged inflammatory proteins (fibrinogen, IgM, alpha2-macroglobulins) and the number and the size of red blood cells, the previously mentioned associations being independent from hematocrit strongly suggest that subclinical, chronic inflammation is related not only to the presence of each of the previously mentioned conditions, but also to the ATS that they cause. Acute phase response indices have been found to be elevated in type 2 diabetics,12 particularly in those patients with the clinical phenotype of the metabolic syndrome.13 Similarly, a recent analysis of a large, population-based study has shown that three indices of inflammation, namely C-reactive protein, white blood cell count, and fibrinogen, tend to cluster with obesity, central distribution of body fat, higher blood pressure, hyperglycemia, lower HDL-cholesterol, and hyperinsulinemia,14 which are all risk factors for ATS. To compound the matter, inflammation indices have been shown to predict the occurrence of IHD events. Thus, C-reactive protein predicted myocardial infarction in a hospital-based study,15 and ESR-predicted future IHD events in a population-based study.3 Whether this predictive power results from a direct association of ESR with the extent of coronary ATS, is unclear. Few studies have tested whether indices of inflammation or blood viscosity reflect theanatomical status of the coronary vasculature.In a study of 573 patients undergoing coronary angiography, the leukocyte count was directlyassociated with the severity of coronary ATS, but the association lost statistical significance after adjusting for smoking.16 In another study, serum C-protein, amyloid protein A, and interleukin-6 concentrations were all found to be elevated in 100 patients with coronary artery disease in comparison to the 100 matched healthy subjects; however, no difference was observed among patients with 1-, 2-, or 3-vessel disease.17 No study has tested whether indices of blood viscosity are associated with more severe coronary ATS.

Our data demonstrate that more severe degrees of angiographically documented coronary ATSexpressed either as number of severely (>50%)stenosed vessels or as the ATS scoreare associated with higher ESR values (Fig. 1). To rule out the possibility that this association was entirely due to the relation of ESR with the individual IHD risk factors, we first analyzed the data after stratifying for other risk factors, such as diabetes andhypercholesterolemia (Fig. 2), and then used amultivariate regression model on the wholedataset (Table 2). By either approach, ESR was an independent correlate of coronary ATS. In statistical terms, ESR explained only a small fraction of coronary ATS; this, however, was also true for all the classical IHD risk factors, in keeping withprevious observations.1820Although our estimate of ATS does not take into consideration the histological characteristics of the lesions (i.e. their stability), the follow-up data demonstrate that in patients presenting withprobable IHD, ESR is an independent predictor of cardiac death ( ). Remarkably in men, an ESR greater than 18mm/h carried the same negative prognosis as a PMI (Fig. 4). This result was similar whether survival was analyzedby quartile of ESR or with ESR as a continuous variable.

To establish whether the prognostic power of ESR was solely explained by its association with coronary ATS, we included ATS in a Cox regression model with cardiac deaths as end-points: whereas sex, hypercholesterolemia, and smoking became statistically nonsignificant predictors, ESR maintained its predictive power (adjusted OR: 1.49 [2.091.06], ). Furthermore, neither thepresence of ischemia nor a PMI modified the risk of cardiac death associated with a high ESR (adjusted OR: 1.41 [1.961.02], ). These analysessuggest alternative pathways through which ESR influenced the prognosis of our patients.

Our conclusions only apply to patients at high risk for IHD, and cannot be readily extrapolated to the general population. Nevertheless, it is of interest that ESR was independently related to ATS (partial , adjusted for sex, age,hematocrit, diabetes, and hypertension) also in the small group of patients in whom coronary angiography was performed as part of the clinical workup for valvular disease, cardiomyopathy, or arrhythmia. In this group, coronary ATS was less extensive than in the primary cohort, and therisk factor profile was more favorable; yet, the adjusted ESR value was still positively associated with a higher ATS score. In addition, in a survey conducted in healthy middle-aged working men followed for 23 years, a very similar estimate of the relative risk for coronary artery disease mortality (OR: 1.59 [1.971.27]) was observed in the subjects with ESR values grater than 15mm/h.5In summary, ESR is an independent correlate of coronary ATS and a predictor of cardiac death in patients with probable IHD. A mild, persistentelevation of ESR should direct physician's attention to coronary ATS and its consequences.

Acknowledgments

We wish to thank Sara Burchielli for her assistance.

The European Society of Cardiology

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ESR, Cornary Ateroschlerosis, And Cardiac Mortality

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