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(Circulation. 2001;103:3062.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Biological Profiles in Subjects With Recurrent Acute Coronary Events Compared With Subjects With Long-Standing Stable Angina
From the Quebec Heart Institute/Laval Hospital (P.B., P.P., S. Simard, L.B., G.R.D.), Laval University, Ste-Foy; and the Montreal General Hospital (S. Solymoss), McGill University, Montreal, Quebec, Canada.
Correspondence to Peter Bogaty, MD, Quebec Heart Institute/Laval Hospital, 2725 Chemin Ste-Foy, Ste-Foy, Quebec, Canada G1V 4G5. E-mail peter.Bogaty{at}med.ulaval.ca
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Abstract |
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Background—At one end of the clinical spectrum of coronary artery disease (CAD) are subjects who have had repeated acute ischemic events, and at the other end are those with long-standing angina who have never been unstable. This study tests the hypothesis that a specific biological profile can distinguish these 2 extreme groups and predict acute coronary events.
Methods and
Results—Blood levels of lipoprotein(a),
homocysteine, tissue plasminogen activator,
plasminogen activator inhibitor-1, C-reactive
protein (CRP), fibrinogen, and von Willebrand factor were
compared in 3 groups of 50 subjects each: (1) those with previous
multiple acute coronary events, (2) age-matched subjects with
3 years of stable angina and no prior acute coronary events,
and (3) matched controls without evidence of atherosclerotic disease
and a normal coronary angiogram. All subjects were followed for
4.0 years. Lipoprotein(a), homocysteine, tissue plasminogen
activator, and plasminogen activator
inhibitor-1 were similar in both CAD groups and
significantly higher than in the control group. However, compared with
subjects with long-standing stable angina, those with previous multiple
coronary events had higher values of CRP (5.7±5.4 versus
3.0±5.2 mg/L, P=0.012),
fibrinogen (3.38±0.75 versus 2.92±0.64 g/L,
P=0.001), and von
Willebrand factor (1.60±0.55 versus 1.25±0.36 U/mL,
P=0.0003). On follow-up,
myocardial infarction and unstable angina occurred in 42% of the group
with multiple events, 4% of the stable angina group
(P<0.0001), and none of the
control subjects. In the 100 patients with CAD, CRP was 4.9 mg/L in
those with and 1.8 mg/L in those without new instability
(P<0.0001). In a
multivariate analysis, only CRP distinguished
those with follow-up acute coronary events (adjusted odds ratio
5.9, 95% CI 2.0 to 17.9;
P=0.002). A baseline CRP >3.5
mg/L had a relative risk of 7.6 (2.6 to 21.7,
P=0.0002) for subsequent acute
events.
Conclusions—An inflammatory biological profile distinguished patients with previous multiple acute coronary events from those with long-standing stable angina and predicted acute coronary instability.
Key Words: myocardial infarction • angina • risk factors • coronary disease • inflammation
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Introduction |
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Clinicians have often been intrigued that among patients with coronary artery disease (CAD), some have recurrent acute coronary events, such as myocardial infarction (MI) and unstable angina (UA), whereas others have effort-induced angina and remain clinically stable for many years.1 2 The pathophysiological substrate of acute CAD is believed to be an inflamed and fissured or eroded atherosclerotic plaque with superimposed platelet aggregation and thrombus formation.3 4 Therefore, a background procoagulant or proinflammatory state and/or a specific metabolic profile could predispose an individual to acute coronary events. Epidemiological and cross-sectional studies have shown that a number of thrombogenic, inflammatory, and metabolic markers are associated with atherosclerosis, CAD, and MI.5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 However, it is uncertain whether these are markers for the presence and extent of atherosclerosis or whether they reflect a particular susceptibility to acute coronary events.24 Thus, it is unclear whether acute CAD is a random event on a varying background of coronary atherosclerosis, is a direct function of the extent of the coronary atherosclerotic burden, and/or is modulated by specific biological risk factors.3 24 25 One means of gaining more insight into this question is to study patients at the extremes of the clinical spectrum of CAD: on one hand, those with a history of multiple acute coronary events, and on the other hand, those with long-standing angina who have never been clinically unstable even though they generally have diffuse CAD.2 We sought to determine whether, in these clinical subsets and in a control group with a normal coronary angiogram, there exist differences in biological markers known to be associated with CAD. These groups were then followed for 4 years to examine the relation of these baseline markers with the occurrence of new acute coronary events.
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Methods |
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Patients
Eligible subjects were identified by scanning consecutive discharge summaries of patients hospitalized with a diagnosis of MI or UA and by scanning the notes of consecutive patients seen at the cardiac outpatient clinic or undergoing coronary arteriography. Three groups of 50 subjects each were established in 1995 to 1996, characterized, and prospectively followed.
Group With Multiple Acute Coronary
Events
Patients with multiple acute coronary events
(MACE) had either 3 MIs or 4 acute coronary events (MI or
UA) with at least 1 MI. The diagnosis of MI required characteristic
prolonged (30-minute) symptoms and creatine kinase elevation more
than twice the upper normal limit (or creatine kinase-MB 10 U/L or
5% of total creatine kinase). UA was defined as characteristic
symptoms, either new in onset or a sharp and significant change in the
pattern of established angina, appearing at rest or on minimum exertion
and requiring hospitalization. Men had to be aged <60 years and women
had to be aged <65 years at the time of their first coronary
event, and all subjects had to be aged <70 years at the time of blood
sampling of the biological markers to avoid the possibly confounding
effect of excessive age. There had to be 1 month between acute
coronary events for both to be counted. Those occurring within
6 months of a revascularization procedure were not
considered. The last acute coronary event had to have occurred
>3 months before blood sampling.
Group With SA
The patients with stable angina (SA), age-matched
with the multiple events group, had to have a minimum 3-year history of
stable angina without any episode suggestive of acute CAD, confirmed by
specific questioning. CAD had to be documented by arteriography showing
stenosis 70% of at least 1 major epicardial artery. These
patients had to have a normal ECG, except for possible minor
nonspecific ST-T features, and documented normal left
ventricular contractility.
Control Group
These subjects, matched for age and sex with MACE
patients, had to have a coronary angiogram, performed within 3
years of blood sampling, judged unequivocally normal by 3 experienced
observers. In 39 subjects, the angiogram was performed to rule out CAD,
and in 11 subjects, it was performed before replacement of a
stenotic aortic valve by a bioprosthesis. All control
subjects were required to have no clinical evidence of atherosclerotic
disease in other vascular beds.
Excluded from the present study were subjects taking
steroid/immunosuppressive drugs or who had type 1 diabetes, tendinous
xanthomas, or any clinically significant disease or history of cancer,
unless it was considered to have been cured for 5 years. At the time
of blood sampling, there had to be no ongoing or recent (<1 month)
inflammatory or infectious disease, no surgical procedure or
angioplasty in the preceding 3 months, and no arteriography in the
preceding month.
The study was approved by the hospital ethics committee, and all subjects gave informed consent.
Blood Biological Markers
Blood sampling was carried out in patients after a
15-minute rest in the supine position between 7:00 and 9:00
AM after a 12-hour fast
with no alcohol intake in the previous 48 hours and no tobacco use that
morning.
Factors measured and methods used were as follows: total cholesterol, HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), apolipoprotein B (apoB), triglycerides, lipoprotein(a) [Lp(a)], and homocysteine, measured by use of methods previously described24 26 ; C-reactive protein (CRP), measured by the N Latex CRP monoassay using a nephelometric technique (interassay reproducibility 3.6% to 4.4%, assay range 0.18 to 1100 mg/L, and sensitivity 0.18 mg/L) with a Behring Nephelometer 100 Analyzer (Dade Behring); and fibrinogen, von Willebrand factor antigen (vWF), tissue plasminogen activator antigen (tPA), and plasminogen activator inhibitor-1 antigen (PAI-1), measured as previously described.24 Intra-assay and interassay variabilities for vWF, tPA, and PAI-1 were 8% and 10%, respectively.
Follow-Up
All subjects were followed for 4.0 years. The
events during follow-up, MI (fatal and nonfatal), and UA, as defined
above, were considered in the primary analysis. Secondary
analyses examined the relation of baseline measures to
composites of (1) cardiac death, MI, and UA, (2) all-cause death, MI,
and UA, and (3) cardiac death and MI.
Statistical Analysis
Values are expressed as mean±SD or as medians with
25% to 75% interquartile ranges, as appropriate. For continuous
variables, comparisons among the 3 groups were performed by using
1-way ANOVA. Categorical variables were analyzed by using
the Fisher exact test. Biological variables distinguishing the 2
CAD groups were analyzed, after rank transformation, by using a
multivariate ANCOVA with potentially confounding
factors as covariates; results were reported as unadjusted means. In
follow-up analysis, continuous variables were compared by
using the Student t test or
Wilcoxon rank sum test as appropriate. The Fisher exact test
was used for categorical data. A multivariate logistic
regression analysis was performed to identify discriminant
predictive parameters. All tests were 2-tailed, and
probability values were considered significant at the 0.05
level.
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Results |
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Baseline Clinical Profile
Over two thirds of the 50 subjects with MACE had a history of
3 MIs, and nearly half had a history of 5 acute events.
All but 1 had sustained their last acute event despite aspirin and/or
coumadin therapy. There was no clustering of events in the year before
blood sampling. Of a total of 237 prior acute coronary events
in these subjects, 15 (6.3%) occurred in the 12 months before blood
sampling. The last event before blood sampling occurred 1.8±1.4 years
previously. The SA group had a history of angina for 9±5 years. Seven
(14%) SA patients and 27 (54%) MACE patients had undergone a
percutaneous revascularization
procedure, whereas 23 (46%) SA patients and 28 (56%) MACE patients
had undergone coronary artery bypass surgery.
Table 1
summarizes clinical and some laboratory
characteristics. In the MACE group, left ventricular
ejection fraction was 50% in 25 subjects, 40% to 49% in 8
subjects, 30% to 39% in 10 subjects, and <30% in 7 subjects. By
study criteria, SA and control subjects had normal left
ventricular function. Although insulin was being used by 7
MACE subjects and by 1 SA subject
(P=0.06),
glucometabolic control was not significantly different in
diabetic subjects in the MACE group compared with the SA group. In the
MACE group versus the SA group, glycated hemoglobin was 7.0±2.0%
versus 5.9±2.0% (P=0.2),
respectively, and serum fructosamine (reflecting glycemic control over
the previous 2 to 3 weeks) was 277.5±70.4 versus 270.9±57.7 µmol/L
(P=0.8),
respectively.
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Biological Markers
Lp(a), homocysteine, tPA, and PAI-1 were markedly
raised in both CAD groups compared with the control group but were not
significantly different in the MACE group compared with the SA group
(Table 2). However, CRP was significantly raised in the MACE
group compared with the SA group (5.7±5.4 versus 3.0±5.2 mg/L,
respectively; P=0.012), as was
fibrinogen (3.38±0.75 versus 2.92±0.64 g/L, respectively;
P=0.001) and vWF (1.60±0.55
versus 1.25±0.36 U/mL, respectively;
P=0.0003)
(Figure 1). These latter 3 markers were not significantly
different in the SA group compared with the control group. In a
multivariate analysis, this triad was
significantly raised in the MACE group compared with the SA group
(P<0.0001) and remained so
after controlling for the potentially confounding factors of current
smoking, diabetes, HDL-C, use of ACE inhibitors and
coumadin, presence of noncardiac vascular disease, and left
ventricular ejection fraction <40%
(P=0.02).
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Follow-Up
MI and UA occurred in 42% of the group with MACE (8
MIs, 13 UA episodes), in 4% of the group with SA (2 UA episodes)
(P<0.0001), and in no subject
in the control group. Time to first occurrence was 1.6±1.2 years. Of
the 15 UA episodes, 6 episodes (40%) were accompanied by acute
transient ST-T changes (with raised serum cardiac markers in 2), and in
3 episodes (20%), cardiac markers were raised without ECG changes. In
the 50 subjects with MACE, there were 14 deaths (28%), of which 11
were cardiac-related; 3 of the latter were fatal MIs, 2 were sudden
deaths, and 6 were due to heart failure. In the group with SA, the only
death was not cardiac-related. There were no deaths in the control
group.
In the 100 subjects with CAD, of all baseline clinical and
biological variables, CRP was the most powerful predictor for
distinguishing those with from those without subsequent acute
coronary events, with a median value 2.7 times higher for those
with events
(Table 3). Other variables significantly associated with
follow-up coronary instability were current smoking at
baseline, use of ACE inhibitors and coumadin, total
cholesterol/HDL-C ratio, apoB, LDL-C, and fibrinogen. After
controlling for these variables and for left
ventricular ejection fraction <40% and use of
lipid-lowering and antiplatelet agents, only CRP (adjusted odds
ratio 5.7, 95% CI 1.9 to 17.2;
P=0.002) and current smoking
status (adjusted odds ratio 3.3, 95% CI 1.1 to 9.5;
P=0.03) distinguished those
with follow-up acute coronary events. Each 1 mg/L rise in
baseline CRP was associated with a relative risk of 1.2 (95% CI 1.0 to
1.3, P=0.009) for follow-up
coronary instability. A CRP value >3.5 mg/L was associated
with a relative risk of 7.6 (95% CI 2.6 to 21.7,
P=0.0002) for subsequent acute
coronary events. This CRP cutoff value identified 17 of the 23
subjects who had acute coronary events on follow-up
(sensitivity 74%) and, in contrast, was found in 21 of the 77 subjects
who did not become unstable (specificity 73%)
(Figure 2). Thus, over the 4-year follow-up, the positive
predictive value was 48%, and the negative predictive value was
91%.
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In secondary analyses, when cardiac death was included as a follow-up event, along with MI and UA, findings were similar. The 28 subjects with these new events had a CRP of 7.3±7.5 (median 4.5) mg/L compared with 3.2±3.9 (median 1.8) mg/L in the remaining 72 CAD subjects without an event (P<0.0001). Corresponding values for fibrinogen were 3.58±0.84 (median 3.51) g/L and 2.98±0.61 (median 2.94) g/L, respectively (P<0.0001). Corresponding values for vWF were not significantly different (1.53±0.54 versus 1.39±0.48 U/mL, P=0.2). These findings were unchanged when all-cause death was substituted for cardiac death. When the composite follow-up event was restricted to cardiac death and MI, the 16 subjects with this event had higher values of CRP, fibrinogen, and vWF than did the 84 CAD subjects without this event (P=0.01, P=0.03, and P=0.03, respectively).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present prospective study examined 2 subsets of patients at the extremes of the spectrum of CAD, in addition to a control group with normal coronary arteries. At one end of the spectrum were patients with long-standing angina who had always been clinically stable; at the other end were patients who had sustained several acute coronary events. The principal findings are as follows: (1) CRP, fibrinogen, and vWF were significantly raised in the group with MACE compared with both SA and control groups, and this held true after controlling for potentially confounding factors. (2) The markers Lp(a), homocysteine, tPA, and PAI-1 were raised in both groups with CAD in contrast to the control group. (3) On follow-up, of all the biological variables, only CRP was a strong independent predictor of new acute coronary events that occurred preponderantly in the MACE group, whereas a lower CRP was a very good predictor of low risk. Thus, these findings suggest that within a population with coronary atherosclerosis, clinically stable at the time of blood sampling, those with a history of repeated acute coronary events have an inflammatory biological profile in contrast to CAD subjects who have always been stable. In addition, this profile identifies those at risk for subsequent acute coronary events. This finding also differs from a profile characterized by raised Lp(a), homocysteine, tPA, and PAI-1 that was comparable in both CAD subsets, in contrast to the control group, and was not predictive of subsequent coronary instability. These results are provocative insofar as they suggest a dichotomy between an acute/inflammatory profile and a chronic/atherogenic profile within the CAD population. They suggest that not all atherosclerosis is necessarily or equally inflammatory, raising the possibility that a more inflammatory expression of atherosclerosis in certain individuals with CAD may increase the risk of sustaining acute coronary events.
Previous Studies
Studies have suggested, in addition to classic risk
factors, the existence of metabolic, hemostatic, and
inflammatory risk markers for CAD. Relationships have been found in
initially healthy subjects between raised baseline values of Lp(a),
homocysteine, fibrinogen, CRP, and tPA and the risk of
CAD.6 10 15 16 22 27
Other studies have associated baseline vWF, factor VIII, tPA, PAI-1,
fibrinogen, CRP, and fibrin turnover with subsequent cardiac events in
patients with initial angina, MI, or angiographic
CAD.5 7 9 11 14 17 23 28
With few
exceptions,11 28
these studies did not attempt to control for the presence and extent of
atherosclerosis, so it is unclear whether these are
markers of the latter or whether they indicate an additional specific
vulnerability for the occurrence of acute coronary events on a
common atherosclerotic
background.8 12 13 18 19 20 21
More generally, this raises the question of whether a dichotomy between
atherogenic and thrombogenic/inflammatory risk markers should be
postulated. In a previous study, we found no differences between the
biological profiles of subjects with SA and those with a single
unheralded MI.24 The 2
groups had different ages, there was no control group and no follow-up,
and patients who have had a single MI may be quite different from those
who have incurred several acute coronary events. The
present study was undertaken because of these
limitations.
CAD Groups Versus Control Group
It is intriguing that levels of fibrinogen, CRP, and
vWF were not significantly different in the stable angina group
compared with the control group. The latter did have a relatively
important proportion of CAD risk factors, which may have raised some of
the parameters evaluated. However, at least regarding
fibrinogen, for which there is abundant published data, the control
group of the present study had values within the range of the
control cohorts, as previously
reviewed.29 Because
it is likely that the SA group had diffuse coronary
atherosclerosis2 30
(as in the MACE group, about half the SA group had previously undergone
coronary artery bypass surgery) and because at least a third
had manifest disease in other vascular beds, this suggests that the
chronic inflammatory component of the atherosclerotic disease process
might be less important in some subjects and much more intense in
others. Thus, an enhanced inflammatory atherosclerosis,
associated with plaques prone to instability in patients with previous
MACE, may have rendered them particularly susceptible to acute
coronary events, whereas a subdued inflammatory expression of
atherosclerosis in patients with SA who had never been
clinically unstable might explain their lesser vulnerability to acute
coronary events. These very suggestive baseline findings were
confirmed by the follow-up observations, whereby increased CRP was a
strong predictor of coronary instability, contrary to the
postulated atherogenic factors, Lp(a), homocysteine, tPA, and
PAI-1.
Study Limitations
Although subjects were well characterized and the
follow-up event rate was high enough to draw statistically pertinent
conclusions, study subsets were not large, and inherent to the
methodological approach, they were highly selected. This must temper
the interpretation of results. As with any clinical or biological risk
marker, there was an inevitable overlap in CRP values between those
with and without events despite relatively good predictive values.
Therefore, findings must be seen as hypothesis-generating and require
confirmation. The definition of UA both as a selection criteria and as
a follow-up event, albeit a rigorous clinical definition, did not
require ECG changes and/or positive serum markers. However, this
definition was advantageous, because as applied to select the SA group,
it allowed greater certainty of the absence of prior coronary
instability. As for the MACE group, 68% had had at least 3 MIs, and an
additional 28% had had 2 MIs as well as 2 UA episodes; only 2
subjects had 1 MI and 3 UA episodes. Thus, it is unlikely that the
definition of UA used in the present study detracted from the
constitution of a group of patients with a strong history of recurrent
acute coronary insults. Finally, over half of the follow-up UA
episodes did have acute ECG changes and/or raised serum markers.
Detection of transient ECG changes would be less likely in many of
these patients with severe CAD and left ventricular
dysfunction, all of whom had an already perturbed baseline
ECG.
Conclusions
An inflammatory biological risk profile was found in
patients with a history of repeated acute coronary events. At
the other extreme of the clinical spectrum of CAD, the present
study identified a subset without an elevated inflammatory biological
profile. This profile was found to strongly predict acute
coronary instability on 4-year follow-up. These results are
consistent with the presence of a smoldering subclinical
inflammatory state in some subjects with CAD. This supports other lines
of inquiry linking markers of inflammation to the risk of acute CAD and
reinforces the rationale for the clinical use of inflammatory markers
for identifying patient subsets at higher and lower risk for new and
recurrent coronary
instability.23 31 32 33 34
In addition, the present study suggests a possible distinction
between atherogenic markers, which were not significantly different at
both ends of the CAD clinical spectrum and not predictive of new
instability, in contrast to inflammatory markers, which were different
and predictive. Future work should investigate why the inflammatory
component seems less pronounced in some subjects with
atherosclerosis and more intense in others, appearing
to render them particularly vulnerable to acute coronary
events.
Received January 26, 2001; revision received April 6, 2001; accepted April 6, 2001.
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