the white blood cell count and risk for coronary heart disease

The white blood cell count and risk for coronary heart disease

Kristine Ensrud, MD, MPH,a,h and Richard H. Grimm, Jr., MD, PhD.b

Minneapolis, Minn..

The prevalence and incidence of coronary heart disease (CHD) in the population is related to levels of certain risk factors, which alone or in combination predict the occurrence of disease. Well established risk factors for CHD include increased age, male sex, elevated serum cholesterol, other abnormal blood lipids, cigarette smoking, blood pressure, and glucose intolerance or diabetes mellitus. However, when summary risk indexes are calculated from levels of known risk factors, their predictive value is much less for an individual than for the underlying population. One explanation is the measurement variability of the known risk factors. Another possible explanation for this phenomenon is the existence of other important risk factors that are not conventionally taken into account.

Numerous investigators have suggested that the total white blood cell (WBC) or leukocyte count is another important factor in predicting ischemic heart disease risk.‘-” This communication will review epidemiologic studies of the association between WBC count and CHD risk, the relationship between WBC count and cigarette smoking, and the potential pathophysiologic mechanisms by which WBCs may promote and exacerbate atherosclerosis.

EPIDEMIOLOGY OF WBC COUNT AND CHD RISK-RETROSPECTIVE AND PROSPECTIVE

STUDIES

Cross-sectional and case-control studies of the relationship between leukocyte count and CHD gener- ally have reported a strong positive association.

From “the Section of General Internal Medicine, Department of Medicine, Minneapolis Veterans Affairs Medical renter; and hthe Division of Epide- miology. School of Public Health, IJniversity of Minnesota.

Received for publication N.w. 18. 1991: accepted Dec. 30, 1991.

Reprint requests: Kristine E. Ensrud. MD, MPH, Department of Medicine I Ill-O), Minneapolis Veterans AtFairs Medical Center, One Veterans Drive, Minneapolis. MN 55417.

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Friedman et a1.l reported a case-control study in which WBC count was predictive of subsequent myocardial infarction (MI); they examined 464 patients with a first MI and compared them with two control groups, one matched for age, sex, and race, and the other matched for these factors plus the major standard coronary risk factors including serum cholesterol level, systolic and diastolic blood pressure, serum glucose, and cigarette smoking status. The mean total WBC count, measured on the average 16.8 months before MI, was significantly greater in patients (p < 0.001) than in either control group, In addition, the risk for MI in patients and controls in the upper quartile of WBC count compared with those in the lower quartile was similar to that observed between the highest and lowest quartiles of serum cholesterol level and systolic blood pressure. A strong relationship was also noted between total WBC count and cigarette smoking status; two thirds of the predictive value of the WBC count for MI could be accounted for by this covariable; the remaining one third was unexplained. In a parallel study that examined 214 cases of sudden cardiac death in men, Friedman et a1.4 reported that the total WBC count was significantly greater in patients than in either control group (p < 0.01) in the subset of mean aged 40 to 54. Over the entire age range studied (ages 40 to 79), the WBC count was significantly greater in patients than in controls matched for age, sex, and race (p < 0.01).

Kostis et al.” examined the relationship between coronary risk factors including total WBC count and angiographic evidence of coronary artery disease (CAD) in a retrospective study of 573 patients who had undergone cardiac catheterization. Exclusion criteria included evidence of infection and recent myocardial infarction (within 3 months of the study). The total WBC count was positively correlated with the severity of angiographic CAD and remained an independent predictor after adjusting for the effects of age, sex, serum cholesterol, and triglyceride levels.

207

208 Ensrud and Grimm

Table I. Number of CHD deaths, CHD fatal and nonfatal events, and deaths f’rom any call+ }I!; white ~-)l()od c-e\\ (LVBC:) count tertile and by cigarette smoking status at entry for MRFIT Ir(-’ participants

~__--.-~~ ---...-~ ~~..._~~~ _.___ ~~_.. ~~. ~~~~ _~~ _ C’HI) deuth C’HD death or nrjnfatnl MI Ali ticwths

No. llj Rate per lfJOl! ‘YO. 0 f K&r, per lfJOf1 .\‘C> ‘,, Rrrlt, per lOfJl1

WBC tertile * deaths persr1n-,wc7rs dL’(lfI1.Y [b’rson-,wnrs tivutil:. :;,‘,‘so,l-“~~‘(Ir.,

Nonsmokers I I7 1.88 711 7.90 ;:! :I.ii-l II x 1.51 :I:1 tj.:iX Iii :<.10

III II) 4.84 “4 12.08 I 9 9.X

Smokers T 1” 2.04 $1 ‘I I 9 i <i .;.$N;

II 28 ‘.%i 99 IO.74 ti:: ci.iir1

111 49 :1.x7 163 1:i:4 I L).! . I- .-! ___- __- ___-- ____~-~

CHI), Coronary heart disease; MRFlT UC’, Multiple Risk Factor Intervention Trial. usual rare: MI. ruyocardial infarclim *Tertiles are defined using all TIC participants: I (.~GllOO), II (6001 to 77110~. 111 (>7700); th? aberage levels for each tertile are T,OY-L. tiXti2. anti 9492 crllc

mm”, respectively. Data from Grimm RH. et al. JAMA 1985;254:1932-7. Reproduced by prmmissmn.

The contribution of the WBC count in predicting the severity of CAD was weakened by adjusting for cigarette smoking status, but the association remained st.atistically significant (p < 0.05).

The Caerphilly study,G a cross-sectional analysis of a random sample of 797 men born between the years 1911 and 1949, tested the association between a number of variables including hemostatic factors and the prevalence of ischemic heart disease. Total WBC count was significantly associated with prevalent disease (p < 0.001) in a stepwise multiple logistic regression analysis despite adjustment for age. The addition of cigarette smoking status and diast,olic pressure to the basic regression model had little effect on this association.

Even stronger evidence supporting t,he association between leukocyte count and ischemic heart disease risk is provided by the results of prospective cohort studies examining the relationship between WBC count and the incidence of CHD. Cohorts have been studied in France, Japan, and the United States.

Zalokar et al.’ followed 7206 French men aged 43 to 53 years who were free of clinical evidence of atherosclerosis at study entry beginning in 1967 for an average period of 6.5 years. WBC count at initial ex- amination was a strong predictor of future MI. Sub- jects with total WBC counts 29000 cells/mm” had a relative risk for MI of 4.5 (95pLs confidence interval 2.5 to 7.8) in comparison with those subjects with total WBC counts <6000 cells/mm:‘. Incidence of MI was also noted to rise in a stepwise fashion with each increasing quintile of baseline leukocyte count. In this cohort, the predictive value of the WBC count for MI appeared to be accounted for by cigarett,e smoking status in that the significant trend in the inci-

dence of Ml by leukocyte count category was oniy seen in current smokers who inhaled and was not seen in never smokers, ex-smokers, or current smokers who did not inhale.

Prentice et a1.s carried out a prospective study of’ a Japanese cohort between 1958 and 1974 (15,909 Hiroshima and Nagasaki residents free of CHD at baseline who were routinely followed because of a history of radiation exposure). Total leukocyte count, t,aken on average 2 years before ascertainment of follow-up status, was found to be positively correlated wit,h CHD incidence (p <O.Ol). Relative risk in creased steadily with ascending quartiles of leukocyte count. The relative risk associated with a count of 10,000 was approximately two t,imes that. of a count of 4000. The relationship between total WBC count and CHD incidence was not explained by age, sex, blood pressure, or serum cholesterol level. In contrasi to t,he study of Zakolar et al., the association between leukocyte count and CHD incidence was also not tjh plained by cigarette smoking status. In fact, the r+ lationship between WBC count and CHD risk was quite similar in smokers and nonsmokers. Examina- tion of differential cell counts indicated that thcl neutrophil count was significantly related to CHJ) incidence (p < 0.05).

More recently, Grimm et al.’ in the Multiple Risk Factor Int.ervention Trial (MRFIT) observed the 1.t lat’ionship of WBC count t,o CHD incidence in I7.S. men. The trial randomized a total of 12,866 middle aged men t,o either a usual care (UC) group or special intervent,ion (SI) group. Men in the SI group under went intense intervention designed to lower cardio-- vascular risk factors, while men in the TTC group werp informed of’t.heir risk factor status and were referred

Voiume 124 Number 1

WRC as a coronary risk factor 209

Table II. Relative risk estimates associated with an increase of 1 SD for specified risk factors for MRFIT UC men*

Relative risk estimatv

Risk factor Mean I!z sot CHD death CHD death or nonfatal MI

Serum cholesterol (mg/dl) 253.5 + 36.8 (39.3) 1.26 (1.28) 1.31 (1.33)

Cigarettes/day 21.8 k 20.5 (15.2) 1.29 (1.21) I.33 (1.23,

Diastolic blood pressure (mm Hg) 99.3 f 7.7 (10.5) 1.24 (1.34) 1.20 (I .28)

M’BCs/(mm”) 7140 i 2080 1.23 1.18

Abbrvviations as in Table 1. *Based nn Cm proportional hazards analysis with the above covariates and age.

tThe SD values in parentheses are taken from the MRFIT initial screen data for 325,384 white men. Data from Grimm RH, rt al. .JAMA 1985:254:1932-7. Reproduced by permission.

Table III. Summary of studies of WBC count and coronary heart disease _.

Critical WBC Stud> Study design Study population ERd point(s,l count fper mm’) Relatiw risk

Friedman et al.’ Case-control 464 cases (men and women) First MI >8800 1.6*

464 ordinary controls <6300

Zalokar et al.’ Cclhort 7,206 French men Fatal/nonfatal MI 29000 4.5 <6000

Prentice et a1.s (“.5-7.8)-j

Cohort 15,909 Japanese men Angina, MI, CHD death >10000 1.8”* and women <4000

Grimm et al.’ Cohort 6,222 American men CHD death >7700 1.981

5 6000 (1.2-x4)+ _~ - Abbreviations as in Table I “Age-adjusted.

tAdjusted for age, diastolic blood pressure, LDL cholesterol. HDL cholesterol, and serum thiocynate level. $95’, confidence interval.

to their customary source of medical care. The relationship of WBC count and change in WBC count to fatal and nonfatai CHD incidence and all-cause mortality was examined in the 6222 men assigned to the UC group. Since this group did not receive inten- sive intervention, it is analogous to a cohort in an ob- servational study. Participants were followed beginning in 1973 through February 1982, with an average of 7 years of follow-up.

Incidence ratios for CHD death, CHD death or nonfatal MI, and all-cause mortality were determined for tertiles of WBC count and cigarette smoking status at baseline (Table I). For both smokers and nonsmokers, the incidence ratios were highest in the upper tertile of WBC count. For smokers, there was a graded increase in incidence rates with each suc- cessive t,ertile. Combining data for smokers and nonsmokers, the age-adjusted relative risk for upper tertile (III) versus lower tertile (I) was 2.10 for CHD death, 1.72 for CHD death and nonfatal MI, and 1.54 for death from any cause.

The independence of the association of WBC count to subsequent fatal and nonfatal events was examined utilizing a Cox proportional hazards regression model wit,h covariates of age, diastolic blood pres-

sure, low density in lipoprotein (LDL) cholesterol, high density in lipoprotein (HDL) cholesterol, and smoking status as indicated by the serum thiocyanate level or the number of cigarettes per day. The association of baseline WBC count and CHD death was of borderline significance (p = 0.09) after controlling for the other major coronary risk factors. For the end points of CHD death or nonfatal MI and all-cause mortality, the regression coefficients corresponding to baseline WBC count were significantly different from zero (p = 0.01 and 0.04, respectively). When this Cox proportional hazards regression analysis was used to obtain adjusted relative risk estimates of tertile III to tertile I, the estimates obtained (1.98 for CHD death, 1.53 for CHD death or nonfatal MI, and 1.49 for all-cause mortality) were similar to the previous age-adjusted estimates. Totally separate analyses were also performed for cigarette smokers and nonsmokers at study entry. For any given end point (e.g., CHD death), the regression coefficient corresponding to WBC count was not significantly different between smokers and nonsmokers.

The relative importance of the association of each risk factor with the end points of fatal and nonfatal CHD incidence was also determined. Relative risk

210 Ensrud and Grimm July 1Y92

Amercan Heart Journa’

7000 z

5 6500

- - White Females

- Y- White Males

_f_ Black Females

- Black Males

I I I I I I

O-6 6-15 16-25 26-35 36-45 46 +

Number of Cigarettes per Day

Fig. 1. Mean leukocyte count in white and black men and women by number of cigarett,es per day. (From Petitti DB, Kipp H. Am J Epidemiol 1986;123:89-95. Reproduced by permission.)

estimates were derived using a Cox regression analysis for a participant with values of risk factors one standard deviation above the mean for total serum cholesterol, diastolic blood pressure, cigarette smoking, and WBC count (Table II). The independent relative risk of being one standard deviation above the mean was comparable for WBC count and diastolic blood pressure and approached that for serum cholesterol level and cigarette smoking.

To better establish the dose-response relationship between WBC count and the three end points, Cox proportional hazard regression analysis was subse- quently performed after adding change in WBC count and change in serum thiocyanate level to the model. A decrease in WBC count of 1000 cells/mm” was significantly associated with a decrease in the risk of CHD death (14 % ) and CHD death or nonfatal MI (6.6 % ). The association between the change in WBC count and CHD risk was independent of baseline WBC count and of change in thiocyanate level.

The salient features of the above epidemiologic studies concerning WBC count and CHD risk can be summarized as follows: (1) Strength: The risk of coronary heart disease is on average twofold higher in individuals with higher WBC counts (>SOOO to 10,000 cells/mm3) compared with those with lower counts (<4000 to 6000 cells/mm3). This twofold increase in risk is not markedly different from the relative risks of CHD ascribed to standard risk factors including serum cholesterol, blood pressure, and cigarette smoking. Relative risk estimates from the major epidemiologic studies are listed in Table III. (2) Con- sistency: The association between WBC count and

CHD risk has been consistently demonstrated in a number of epidemiologic studies. The effect extends to both fatal and nonfatal events. (3) Dose-response: The majority of studies have demonstrated a dose- response effect, in that progressive levels of WBC count are associated with graded increases in CHD risk. In addition, the MRFIT analysis demonstrated that a drop in WBC count was associated with a decrease in CHD risk. (4) Temporality: Prospective studies have shown a temporal relationship between WBC count and CHD risk, documenting that the higher level of WBC count appropriately predates the occurrence of CHD. (5) Independence: Most studies simultaneously measured other coronary risk factors, including cigarette smoking, and reported that the WBC count was an independent risk factor for CHD. (6) Generalizability: The great majority of studies have focused on middle-aged men. The association between WBC count and CHD risk is less well documented in other groups, including women and persons more than 65 years of age.

WBC COUNT AND CIGARETTE SMOKING

The relationship between the WBC count and cigarette smoking is well established. Numerous researchers have reported that WBC counts are significantly higher in current cigarette smokers compared with non-smokers or former smokersg-‘” Recent research has focused on describing this relationship in greater detail. Petitti and Kipp,i3 in their study of 62,541 individuals (black and white subjects of both sexes) in a Northern California health maintenance organization, explored the relationship of the leuko-

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Number 1 WBC as a coronary risk factor 211

cyte count to measures of intensity of cigarette smoking. In current smokers of either race or sex, the WBC count increased with the smoking of a large number of cigarettes per day. At every level of number of cigarettes smoked per day, the leukocyte count was higher in whites than in blacks and higher in women than in men of the same race (Fig. 1).

Using multiple linear regression analyses with covariates of age, race, sex, number of cigarettes smoked per day, tar yield of currently smoked cigarette, and frequency of inhalation, leukocyte counts in current smokers were shown to be independently and significantly (p < 0.05) associated with smoking cigarettes of a high tar and nicotine yield and with a longer duration of smoking. The persistence of the effect of cigarette smoking on the leukocyte count was also examined in a multiple linear regression analysis including past cigarette smokers currently using no form of tobacco and never users. While the effect of cigarette smoking on WBC count appeared to persist after ceasing smoking, the magnitude of this effect decreased as time since ceasing smoking increased. Past smokers in general had higher WBC counts than never users; in past, smokers, the WBC count decreased progressively as the length of time since quitting smoking increased.

The relationship between the WBC and smoking was also explored by Hansen et a1.14 in the MRFIT study. In a multivariate analysis that included as co- varrables the depth of inhalation, duration of the smoking habit, number of cigarettes smoked per day, and type of cigarette smoked (filter or no filter, men- thol or regular, king size or regular); the depth of inhalation. duration of smoking habit, and number of cigarettes smoked per day were independent and significant predictors of total WBC count. In addition to the analysis of current smokers, the relationship between WBC count and time since smoking cessation was examined. The WBC count of current smokers (7853 cells/mm”) differed significantly (p < 0.01 for each comparison) from that of ex- smokers of less than 12 months (7091 cells/mm3), ex- smokers who quit more than 1 year before (6255 cells/mm”), and nonsmokers (6099 cells/mm”).

bn contrast to the majority of studies focusing on adults, Tell et al.‘” investigated whether the relationship between WBC count and cigarette smoking could be demonstrated in an adolescent population (439 Norwegian youths, 14 to 16 years old) exposed to cigarettes for only a relatively short period of time. Among male and female subjects, there was a significant positive correlation between frequency of smoking (reported as cigarettes per day) and WBC count. Analyses of covariance, adjusting for height, weight,

age, sexual maturation, HDL cholesterol level, and hematocrit revealed a progressive gradient in WBC count from nonsmokers to occasional to regular smokers. In addition to the results of this study demonstrating elevated WBC counts in young individuals with relatively short tobacco exposure, an acute transitory increase in WBC count has been reported in individuals after smoking only one to three cigarettes. I6 In summary, the epidemiologic data suggest that there is a strong relationship between WBC count and cigarette smoking, with acute and chronic components. The relationship does not, however, wholly explain the association between elevated WBC count and CHD risk in that a component of this association is independent of smoking, persisting in nonsmokers and in smokers of comparable tobacco consumption.

ROLE OF WBCs IN THE PATHOGENESIS OF

CORONARYHEARTDISEASE

Though the WBC count has been recognized to be associated with CHD, it is viewed by some investigators as being a marker of cigarette smoking, inflammation, or stress, contributing to ischemic disease risk rather than being a potential cause.17, la Other researchers have taken the view that the leukocyte is a key participant in the process of vascular injury and that the total WBC count is an indicator of the intensity of this process. Although leukocytes are traditionally thought of as defenders against infec- tions, they also play an important role in microvascular perfusion. Ernst et al.” have outlined three mechanisms by which leukocytes may contribute to microvascular injury and promote atherosclerosis. These include (1) pressure-dependent plugging of microvessels, (2) rheologic properties such as altered deformability and the formation of aggregates when provoked by a variety of stimuli, and (3) release of activated substances including oxygen-free radicals, proteolytic enzymes, and arachidonic acid metabolites.

Compared with red blood cells, leukocytes are large, stiff cells with diameters greater than most nu- tritive capillaries in tissues. Thus the capillary transit of WBCs is frequently associated with slowing of blood flow.rg When perfusion pressure is decreased, major WBC-induced disturbances in microvascular flow may occur, capillary plugging may be prolonged or permanent, and the somewhat larger arterioles and venules may experience significant reductions in luminal diameter because of adherence of WBCs to the endothelium.sO This obstruction in microvascular flow may be further enhanced by ischemia-induced decreased WBC deformability.21 In addition to in-

212 Ensrud and Grimm

herent difficulty in capillary transit and altered deformability under low-flow conditions, WBCs (es- pecially neutrophils) possess the ability to aggregate or clump when stimulated and thus the theoretical capability of embolizing to microvascular sites.“” Both enhanced granulocyte adhesion to endothelial cells and granulocyte aggregation have been demonstrated to occur in vivo.‘3

During the process of migration and adherence to the microvascular site, activation of neutrophils oc- curs. The cell begins t.o project high characteristic pseudopodia and releases a variety of products, result,ing in inflammation and vascular injury. These products include superoxide radicals (superoxide anion and hydrogen peroxide), proteolytic enzymes, and arachidonic acid metabolites such as leukotriene.‘4-“’ Superoxide radicals are highly reactive substances, capable of injuring and lysing a variety of cell types, including endothelial cells.“7 Proteolytic enzymes cont,ribute to vascular injury by promoting endothelial cell detachment.2A Exposed subendothe- lial collagen and fibronectin are t,hen susceptible to platelet adherence and activation. Leukotrienes (es- pecially leukotriene Bd) released by activated granulocytes promote vasoconstriction and have chemotactic properties, attracting addit,ional neutrophils and platelets to the sit,e of vascular injury.“g-,‘”

In addition to these potential mechanisms, results of recent, studies in humans have supported t,he be- lief that neutrophils are involved in the genesis and propagation of myocardial ischemia. Blood filtration studies of patients with myocardial infarction have demonstrated decreased deformability of WBCs.“’ Mehta et a1.3” have shown that patients with stable angina exhibit markedly increased chemotactic activity and leukotriene B* generation compared with neutrophils from age-matched cont,rol subjects. Rice- vuti et al.“3 have demonst,rated increased neubrophil aggregation and oxidase activity in the coronary sinus of patients with angiographic evidence of coronary heart disease compared with controls free of disease. Although none of these studies of myocardial ischemia in humans have compared neutrophil function and activity in smokers to those in nonsmokers, previous studies have shown that, neutrophil produc- tion of oxygen radicals is increased in smokers with elevated WBC, counts. :N In addit.ion, Ludwig et al.“” demonstrated t.hat neutrophils from hyperlipidemic subjects have higher oxidative metabolism with greater release of superoxide anion than neutrophils from age-matched controls with normal lipoprotein levels. Release of superoxide anion was significantly correlated (p < 0.001) with serum cholesterol and LDL cholesterol levels.

July 7997

American Heart Journal

SUMMARY

In conclusion, the WBC count has been demonstrated in several epidemiologic studies to be a strong independent predictor of future coronary heart disease. Although it is not possible at this point in time to be certain that the elevated WBC count is a cause rather than a consequence of ischemic heart, disease. recent pathophysiologic studies suggest that the white blood cell, in particular the neutrophil. i? instrumental in the pat.hogenesis of’ myocardial is chemia. It is conceivable that patients who develop acute myocardial ischemia have abnormal leukocyte function before the onset of the acute event, which provides a pathophysiologic milieu for the progres- sion of the atherosclerotic process. Future research must focus on further elucidation of the properties of

WBCs and clarification of the role of t.he activated neutrophil in the process of vascular injury. Quanti- tative and qualitative changes in leukocyte function may have important implications in t he development of CHD.

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the white blood cell count and risk for coronary heart disease

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