IgE predicts future nonfatal myocardial infarction in men

0895.4356/961$15.00 SSDI 0895-4356(95)00548-I

J Clin Epidemiol Vol. 49, No. 2, pp. 203-209, 1996 Copyright 0 1996 Elsevier Science Inc.

ELSEVIER

IgE Predicts Future Nonfatal Myocardial Infarction in Men Robert D. l-anger, * Michael H. Criqui, Heather S. Feigelson, Theresa J. Mc~unn, and bowers N. ~~~~urg~ DEPARTMENT UNIVERSITY

OF COMMUNITY OF CALIFORNIA,

AND

FAMILY SAN

0607

DIVISION

GKLMAN

DRIVE,

MEDICINE,

DIEGO,

9500

OF EPIDEMIOLOGY, LA JOLLA,

CA

SCHOOL

OF MEDICINE,

92093.0607, U.S.A.

ABSTRACT. Established risk factors cannot explain all the variance in coronary heart disease (CHD). Immunoglobin E (IgE), a mediator of allergy, can affect platelets and arterial smooth muscle. We previously demonstrated a cross-sectional association between IgE and cardiovascular disease (CVD) in men. The present study evaluated this relationship prospectively in 278 men and 343 women followed for a mean of 8.9 years. There was an association between IgE and coronary disease in men, but not in women. There was no association for CVD, stroke, or all-cause mortality. The age-adjusted relative risk (RR) for coronary mortality in men with baseline IgE a 200 kU/L was 1.66 (p s 0.66), but for nonfatal myocardial infarction (MI) it was 6.46 (p G 0.01). This association was independent of smoking and other risk factors, and unrelated to allergy. Thus, elevated IgE was a strong independent prospective risk factor for nonfatal, but not fatal, MI in men. J CLIN EPIDEMIOL 49;2:203-209, 1996. KEY WORDS. IgE, coronary heart disease, cardiovascular disease, allergy, smoking

INTRODUCTION Some victims of cardiovascular disease (CVD) have “desirable” levels of risk factors like blood pressure, lipids, smoking, and blood glucose; these well-known risk factors only explain a portion of the variability in CVD [I]. Other as yet unrecognized factors must play a role in the etiology of vascular events. Elements of the hemostatic system and influences on vascular autoregulatory mechanisms may explain some of this variance. Immunoglobin E (IgE), which is known primarily as a mediator of allergy, can cause platelet activation [Z-4], aggregation [S], and arterial smooth muscle hyperplasia [6]. IgE-mediated histamine release may influence vascular autoregulatory responses. Histamine has been shown to induce coronary artery spasm in both animals and humans [7-l 11. Thus, IgE has a plausible physiologic role in the etiology of CVD. Several previous studies have looked at the relationship of nonallergic factors to IgE levels. Many of these have focused on smoking. In a previous report we explored the associations between IgE and health-related characteristics, and contrasted these results with findings in other populations [12]. The distribution of IgE in this cohort was similar to that shown in other population studies, with means ranging between about 20 and 40 kU/L [12]. Men in this cohort had higher age-adjusted levels of IgE than women, and were more likely to smoke cigarettes [12]. Multiple regression results in our previous study showed that, in men, in addition to personal and family history of allergy, the level of IgE was positively related to current smoking, past smoking, alcohol consumption, and fasting plasma glucose. IgE in men was inversely related to low-density lipoprotein cholesterol. In women, an inverse relation between IgE and age was the only strong nonallergic association. We previously demonstrated a cross-sectional

‘All correspondence should be addressed to: Robert D. Langer, MD, MPH, Division of Epidemiology, UCSD School of Medicine MC 0607, La Jolla, CA 92093-0607, U.S.A. Received in revised form 12 April 1995

association between IgE and coronary heart disease (CHD), stroke, and peripheral arterial disease in men but not women [13]. Smoking has been associated with elevated IgE levels in diverse populations 114-231, and because of the strong relation between smoking and CVD, could confound an IgE-CVD association. Our earlier report on the associations between IgE and cardiovascular disease adjusted for cigarette smoking, but did not explore the IgE-smoking-CHD relation in detail [13]. A study by other investigators published after our initial report sug gested that myocardial infarction (MI) temporarily elevated IgE, and that high IgE was associated with survival among men with MI. These investigators questioned the existence of a prospective relationship [24]. Now we report the first evidence of a prospective association between IgE and CHD based on 9 years of follow-up in men free of disease at baseline who were participants in a community-based population study. METHODS

Study Population This cohort of 624 men and women was defined for a study of peripheral arterial disease (PAD). Baseline examinations took place between 1978 and 1981. These participants were a subset of the La Jolla Lipid Research Clinic (LRC) population which enrolled 83% of all adult residents living in an upper-middle-class, primarily Caucasian, retirement community in Southern California between 1972 and 1974. The PAD subjects were selected from those who attended LRC visit 2; a visit that included equal numbers of participants with normal lipids and with h~eriipidemia. Hyperlipidemia was defined as cholesterol 2 the 90th percentile for age and sex, or triglycerides 2 the 95th percentile, or use of lipid lowering medications. The PAD subjects were comparable to visit 2 subjects with respect to age, sex, and the proportion with hyperlipidemia (47.9%). There were 279 men (aged 40 to 82 years, mean 65.8 years), and 345 women (aged 38 to 82 years, mean 66.1 years). IgE was not measured in one man and two women, leaving 278 men and 343 women eligible for the present study.

204

Langer et al.

W

Statistical Methods

Specimens for IgE were obtained at the clinic and measured quantitatively by the paper radioimmunosorbent test which uses purified monospecific anti-human IgE antibody fixed to a paper disk [25]. IgE values ranged from undetectable to 1000 kU/L. Undetectable values were reported as <5 kU/L and were arbitrarily assigned a value of 2.5 kU/L for these analyses. Because this distribution was not normal, geometric means and log IgE values were calculated for use in some analyses.

Data were analyzed using SPSS/PC+ [27] and Epilog Plus statistical software [28]. Age-adjusted means were calculated for potential risk factors. Analysis of variance was used to compare differences in characteristics between groups. After testing to insure that the assumption of proportional hazards was satisfied, Cox regression models were used to evaluate potential associations and interactions, and to control for important covariates. Follow-up time in these Cox models was calculated as the time in days from the baseline examination until an event for cases, or until the most recent contact for noncases. Some participants experienced more than one end point (e.g., both a nonfatal and a later fatal MI); these subjects were included in each relevant model using event-specific survival times, but only one event per subject was counted in any model.

Risk Factors

Carhascular

Fasting blood was obtained for measurement of plasma high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) cholesterol using the Lipid Research Clinics standardized protocol [26], and plasma glucose (FPG) using the glucose oxidase method (Beckman ASTRA-8). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in the sitting position using a random zero sphygmomanometer. Cigarette smoking and alcohol use histories were obtained as part of a standardized interview conducted by a trained examiner.

Allergy History At the baseline examination a trained interviewer recorded the participant’s responses to a detailed allergy questionnaire. Data obtained included personal history of asthma, nasal allergy, eczema, hives, food allergy, and medication allergy. History of allergy in relatives was recorded using separate questions for mother, father, brothers, sisters, sons, and daughters.

Folhwuf,

for Morbidity and Mortality

Data for mortality has been updated annually as part of the Lipid Research Clinics Follow-up Study. Vital status as of September 1, 1989, was known for 621 subjects (100%). The average follow-up interval was 8.9 years. Death certificates were obtained on all decedents and coded by a certified nosologist using the International Classification of Disease, ninth Revision. Death was assumed to be from coronary disease if the underlying cause was attributed to ICD codes 410-414 inclusive, from stroke if attributed to ICD codes 430-438 inclusive, and from CVD if attributed to ICD codes 400-444 inclusive. Interval morbidity data was self-reported on mailed questionnaires distributed in 1982, 1984, and 1988. Additional morbidity data was obtained by interview at a clinic visit attended by approximately 75% of this cohort between 1984 and 1987. Nonfatal MI was defined as self-reported history of MI on these questionnaires or at the 1984-1987 clinic visit. CHD morbidity included nonfatal MI, or self-reported angioplasty, coronary bypass graft surgery (CABG), or coronary disease at angiography. CHD morbidity and mortality was defined as coronary heart disease morbidity or coronary disease death. Stroke morbidity and mortality was defined as self-reported stroke, or stroke surgery, or stroke death. CVD morbidity and mortality included coronary disease morbidity and mortality, stroke morbidity and mortality, and other CVD death (ICD-9 codes 400-409, 415-429, or 439-444) not covered by the former more specific categories. Self-reported morbidity data were evaluated for consistency by two of the investigators (RDL and MHC) who were blind to IgE status. Participants with inconsistent histories for incident events which could not otherwise be validated from study records were excluded from analyses involving those end points.

RESULTS Table 1 provides an overview of the number of participants, ageadjusted mean IgE, and several categories of events by sex. Table 2 shows age-adjusted geometric mean IgE levels in cases and noncases for several CVD endpoints without exclusions for baseline disease or other prospective end points in men and women. Preliminary analyses showed an association between IgE and CHD, but not CVD, stroke, or all-cause mortality. Accordingly, further analyses were limited to an exploration of the association between CHD and IgE. Twenty-nine men and 19 women had CHD at baseline (MI, coronary artery bypass graft, or angiography); morbidity follow-up data were missing for 18 men and 22 women and uncertain for 16 men and 8 women. After excluding these subjects 215 men and 295 women were available for analyses regarding CHD. In this subset of men, age-adjusted geometric mean IgE levels were significantly higher in cases than noncases for nonfatal MI (p < 0.01) and CHD morbidity and mortality (p s 0.05). There were no differences between cases and noncases for any of these end points in women. Figure 1A shows the numbers of men and the crude rates of incident CHD morbidity and mortality by 50 kU/L increments of IgE. Figure 1B shows these same data for women. As can be seen from Table 2 and Fig. 1, the association between CHD and IgE was essentially limited to men. Accordingly, further analyses were limited to these 215 men free of CHD at baseline. Within this group there were 14 nonfatal MI events and 9 CHD deaths. Six additional men had CABG, angioplasty, or coronary disease at angiography. Since these data suggested a threshold for increased CHD risk at about the 90th percentile, or 200 kU/L of IgE, we further categorized these men into groups above and below this cutpoint. To evaluate whether established CVD risk factors differed by IgE level above or below the 200 kU/L cutpoint, we computed categorical means and tested for statistically significant differences using analysis of variance. Variables tested included age, cigarettes per day, pack years of cigarette smoking, triglycerides, HDL cholesterol, LDL cholesterol, DBP, SBP, average daily alcohol intake, and fasting plasma glucose. All factors other than age were adjusted for age. These data are displayed in Table 3. Of the variables tested which could potentially confound the relation between IgE and CHD, only DBP was significantly different in participants with IgE above or below 200 kU/L. We next fitted Cox proportional hazards regression models for CHD events stratified on IgE above and below the 200 kU/L cutpoint in

205

IgE Predicts Myocardial Infarction in Men Table 1. Participants

Men Women Total

and events in 9-yr follow-up

of the PAD cohort

nN

Geometric mean IgE kU/L (SD)

Deaths

278 343 621

24.5 (4.5) 17.5 (4.1) 20.3 (4.3)

71 45 116

these men. In the age-adjusted model for CHD mortality, IgE 1 200 was not significantly associated with risk [relative risk (RR) 1.66, 95% CI 0.21-13.321. This result was unchanged after adjustment for other risk factors including cigarettes, DBP, LDL cholesterol, and FPG. It was also unchanged after excluding men with nonfatal MI from the noncase group. By contrast, the age-adjusted model for CHD morbidity and mortality provided a significantly elevated RR estimate of 3.43 (95% CI 1.39-8.45). After adjustment for the other risk factors listed above, this RR was decreased slightly (RR 3.00, 95% CI 1.19-7.55). This elevated risk for combined CHD morbidity and mortality, in the absence of increased risk for CHD mortality alone, suggested an association primarily with nonfatal disease. Table 2. Age-adjusted

geometric

CVD deaths

CHD deaths

39

27 13 40

Baseline CHD 29 19 48

Nonfatal MI 14

Consistent with this observation, the age-adjusted RR for nonfatal MI associated with IgE 3 200 kU/L was 6.46 (95% CI 2.14-19.54). This risk estimate was slightly increased after excluding nine men with fatal CHD from the noncase group. In that model, the age-adjusted RR associated with IgE 2 200 kU/L was 6.7 (95% CI 2.21-20.31). Similarly, adjustment for other CHD risk factors slightly strengthened this risk estimate (RR 7.31, 95% CI 2.23-23.91) in the model using cigarettes per day as the smoking variable along with age, DBP, LDL cholesterol, and FPG. In the latter model cigarettes per day (p s .Ol) was the only variable other than IgE category to achieve statistical significance. Results of these Cox models are displayed in Table 4. The strength of cigarettes per day in the model for nonfatal Ml, along with prior suggestions that smoking could confound an IgE asso-

mean IgE levels for selected end points in men and women N Cases

Men CVD-MM

Noncases

Geometric mean W (SD) Cases Noncases

71

183

CVD death

39

239

Stroke MM

15

227

CHD-MM

53

186

30.9 (5.4) 29.5 (5.0) 17.8 (5.1) 33.9’

CHD death

27

Nonfatal MI

14

201

28.2 (4.8) 61.77

Angioplasty, CABG, or angio CHD

22

186

23.4 (4.6)

31

293

CVD death

19

324

15.1 (4.4) 16.6

Stroke MM

12

309

18.6

(5.6)

(7.2) Women CVD-MM

WY (5.6) CHD death

13

330

Nonfatal Ml

10

285

Angioplasty, CABG, or angio CHD

10

277

‘p s .05 for difference from noncases. tp c .Ol for difference from noncases. MM, morbidity and mortality. Rows have different totals due to uncertain follow-up data for some end points.

17.0 (4.2) 19.1 (3.6) 14.5 (3.7) 24.0 (4.2)

22.4 (4.3) 22.4 (4.5) 24.0 (4.5) 21.4 (4.2) 22.9 (4.5) 21.9 (4.2) 21.4 (4.2) 17.0 (4.1) 16.6 (4.1) 16.2 (4.1) 17.8 (4.1) 17.0 (4.1) 18.2 (4.1) 17.8

(4.2)

Langer et al.

206

CHD MM Rate/100

100-149

50-99

o-49

150-199

200-249

A. IgE Level (kU/Liter)

250-299

300-1000

in MEN

CHD MM Rate/100

100-149

50-99

150-199

200-249

B. IgE Level (kU/Liter)

250-299

300-1000

in WOMEN

FIG. 1. Number of participants and crude CHD morbidity and mortality rates by IgE category of disease at baseline. (A) IgE level (kU/Liter) in men. (B) IgE level (kU/Liter) in women.

Table 3. Mean (SD) levels’ 215 PAD men free of CHD

of risk factors at baseline

IgE i 200 kU/L N= 195 Age (yr) Cigarettes per day Cigarette pack years Triglycerides (mg/dL) HDL (mg/dL) LDL (mg/dL) DBP (mm Hg) SBP (mm Hg) Alcohol (g/d) FPG (mg/dL)

65.67 3.32 24.54 146.05 50.14 153.42 77.24 133.02 22.45 94.47

(11.19) (9.09) (27.13) (88.03) (14.32) (34.08) (7.96) (17.12) (24.03) (13.93)

‘All factors except age adjusted for age. p values for difference by IgE group.

by IgE category

IgE 2 200 kU/L N = 20 62.70 4.77 24.41 136.07 48.39 150.31 81.79 135.32 23.65 97.68

(13.80) (10.57) (24.48) (67.90) (14.15) (27.29) (8.18) (16.17) (33.89) (14.58)

in

p value 0.27 0.49 0.98 0.62 0.60 0.69 0.02 0.54 0.84 0.33

in 215 men and 295 women

free

ciation, led us to investigate this relation thoroughly. An interaction term for cigarettes x log IgE was not statistically significant (p > 0.47). Using pack years rather than cigarettes per day as the smoking measure did not affect the risk estimate for IgE 2 200 kU/L (RR 6.97, 95% CI 2.11-23.02) in a model with age, pack years, DBP, LDL cholesterol, and FPG. In contrast to the statistically significant effect associated with cigarettes per day in the prior model, pack years was not statistically significant in this second model (p s 0.48). To further assess possible confounding by cigarette smoking, we tested the association of elevated IgE with nonfatal MI in separate models for never smokers, exsmokers, and current smokers. Similar risk estimates were obtained in each model (data not shown). These results, along with the independence of cigarettes and IgE in unstratified models, suggest that smoking status does not confound this relationship despite the well-documented positive association between cigarette smoking and IgE.

IgE Predicts Myocardial

Infarction

207

in Men

Table 4. RRs for men with IgE > 200 kU/L for specified end points from Cox proportional hazards models Event CHD death CHD-MM Nonfatal MI Nonfatal MI” Nonfatal MI’+l

RR 1.66 3.43 6.46 6.70 7.31

95% CI 0.21-13.32 1.39-8.45 2.14-19.54 2.21-20.31 2.23-23.91

Table 5. Self-reported specific personal allergy history according to subsequent MI status in 20 men with IgE 2 200 kU/L Later MI*

p due 0.63 0.01 0.00 0.00 0.00

* After excluding nine contmIs with fatal CHD. tAfter adjustment for cigarettes per day, DBP, LDL cholesterol, and FPG. Considering these findings, we looked further at the trend associated with IgE levels and nonfatal MI. Figure 2 shows crude rates of nonfatal MI by 50 kU/L categories of IgE in men free of disease at baseline. The contrast between Fig. 2 and Fig. 1 (which plotted combined CHD morbidity and mortality in these men) highlights the stronger relation between IgE and nonfatal MI. Specifically, Fig. 2 shows a much lower rate of nonfatal MI for IgE s 199 kU/L and a clear upsurge in risk beginning at 200 kU/L. History of asthma, hay fever, or urticaria has been associated with elevated IgE in this population 1121. However, there was no association between personal or family history of allergy and nonfatal MI in these men in either multivariate or univariate analyses. Table 5 shows the personal allergy histories in men with IgE 2 200 kU/L according to subsequent MI status. At these high IgE levels, allergies were not more common in men with nonfatal MI. There was considerable clustering of IgE-related allergies including asthma, hay fever, and urticaria in men with high IgE who did not experience MI, but not among men with high IgE who had an incident MI. These findings imply that the association between IgE and nonfatal MI was not mediated by allergy, and actually suggest the converse; that a nonallergy-related increase in IgE was prospectively related to nonfatal MI. Finally, we tested the relation between IgE and non-MI nonfatal CHD (CABG, angioplasty, and coronary disease at angiography) in these men. No association was found.

DISCUSSION IgE levels above 200 kU/L were associated with nearly seven times the risk of incident nonfatal MI in men without any prior history of

No MI’

Type of allergy

+-u+-u

Asthma Hay fever Urticaria Any IgE-associated asthma, hay fever, or urticaria Eczema Other nasal Food Medication

0 :

5 44

0 i

4 :

11 1:

2

3

0

9

6

0 0 0 0

0 k

5 4 5 4

0 0 0 0

0 4 :

14 11 12 9

1 0 1 1

*AI&y;

1

+ , positive; - , negative; or U, uncertain.

coronary events. This risk increment appeared to have a threshold, and is far greater than that associated with commonly accepted CHD risk factors. A unique feature of this IgE association was its existence only for nonfatal MI events. There was no association between IgE and fatal MI, or between IgE and non-MI coronary morbidity, sug gesting that IgE-related events may involve the coronary microvasculature, or perhaps local thrombosis, rather than chronic atherosclerosis. Furthermore, these results indicate that the mechanism of this markedly elevated risk associated with high IgE is independent of coronary disease risk factors that are commonly associated with atherosclerosis. IgE is associated with cigarette smoking, and both are associated with coronary disease. However, these risk factors did not interact, and remained independently predictive of CHD events. Our results strongly suggest a non-atherosclerotic pathway for this variant of CHD. Other lines of research also suggest that constriction of small coronary vessels can cause coronary ischemia 1291. The known associations between IgE and vasoactive substances such as histamine prompt us to speculate on some potential pathophysiologic explanations for these results. High IgE levels may indicate the potential for a massive release of mediators, such as histamine, which in turn may cause acute vasospasm, ischemia, and infarction. Similarly, IgEassociated mechanisms may increase platelet aggregation, creating thrombi unrelated to atherosclerosis. Another mechanism has been suggested by a recent autopsy study in Finland that showed up to a

Crude NFMI Rate/l 00

IgE Level. (kU/Liter) F2G. 2. Number of participants did not die of CHD.

and crude nonfatal MI rates by IgE category in 206 PAD men free of disease at baseline and who

208 50.fold increase in activated mast cells in human atheromas [30]. Mast cells can release proteases such as tryptase and chymase which could trigger matrix degradation leading to destabilization and atheroma rupture, potentially triggering an acute coronary event. These and other possible pathophysiologic hypotheses cannot be evaluated in our population, but deserve further study. The threshold effect observed at 200 kU/L in these men may represent the joint effects of two factors, a massive release of IgE-related mediators may only be physiologically important at the extremes of the distribution, and the skewed distribution for IgE creates a relatively low density of persons at risk with moderate elevations of IgE. Barbash et al. (311 have recently reviewed data showing a higher proportion of smokers with MI and normal coronary arteries [32], suggesting a higher rate of acute spasmodic occlusion, perhaps related to sympathetic nervous system stimulation by smoking [33,34], and have suggested that smoking-induced MIS are more survivable due to less underlying atherosclerotic occlusion. Because the most likely pathway for IgE effects on coronary occlusion also involves mediated vasospasm, and/or platelet activation and thrombosis, such MIS might be similarly more survivable. The finding that cigarette smoking did not confound this association between IgE and nonfatal MI was surprising, as smoking is known to be independently related to both. A prior study in this same population [12] indicated a relationship between IgE and smoking, and IgE and MI and found that smoking does not confound this relation. In the present analysis we extend this observation to show that smoking does not confound a prospective association between IgE and MI. Furthermore, we were unable to find a relation between non-fatal MI and all allergy, or subtypes of allergy, though these latter analyses had limited power due to the small number of participants in each category. These results suggest that elevated IgE is a marker for nonfatal Ml independent of its association with allergy or smoking. Thus, persons with a history of allergy were not at increased risk for CHD events in our study. Until more is known about the underlying mechanism for this IgE association, we would not speculate about interventions to reduce this risk. No statistically significant association could be found in women, though examination of the trends (Fig. 1B) lends weak support for further investigation, as a nonsustained increased crude rate appears at 200-249 kU/L. The lack of association in women could be due both to few events in women in this cohort, and generally lower IgE levels in women. It is consistent with the cross-sectional results previously reported in this population. This study was conducted in an upper-middle-class, Caucasian population. The extension of these findings to other groups will require replication of these results in diverse populations. In the study reported by Szczeklik et al. [24], that looked at patients presenting to a hospital with MI, survival was much better in subjects with IgE 2 200. Our cutpoint of 200 kU/L is near the 90th percentile of IgE in these men. It is fascinating that these other investigators found a logical cutpoint relative to survival at this same level. Based on data from these two populations it appears that IgE > 200 is a marker for increased MI risk, but for a more survivable form of infarction. The lack of control subjects in the study by Szczeklik et al. may have led to their suggestion that IgE was a prognostic factor, rather than a risk factor for a different form of coronary disease, as now seems apparent from both our data and theirs [35]. Because participants with disease at baseline were excluded, this study provides strong evidence against the IgE association with CHD events previously reported by us and others being simply an artifact of a recent ischemic event. Rather, IgE appears to be an independent prospective risk factor for nonfatal, but not fatal, MI in men.

Langer et al. This work was supported by the University of California Tobacco Related Disease Research Program Award no. 1RT 468.

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