European Heart Journal (2001) 22, 14591465

doi:10.1053/euhj.2000.2553, available online at http://www.idealibrary.com on

Clinical characteristics, aetiological factors and
long-term prognosis of myocardial infarction with an
absolutely normal coronary angiogram
A 3-year follow-up study of 91 patients
A. Da Costa, K. Isaaz, E. Faure, S. Mourot, A. Cerisier and M. Lamaud
Division of Cardiology, University Jean Monnet of Saint-Etienne, Saint-Etienne, France
Objectives The purpose of this study was to evaluate the
clinical outcome of a large cohort of patients who suered
an acute myocardial infarction with absolutely normal
epicardial coronary arteries at the post-myocardial infarc-
tion coronary angiogram. The aetiological and prognostic
factors in this population were also analysed.
Background Few data exist concerning the outcome, and
aetiological and prognostic factors, of patients with myo-
cardial infarction and angiographically absolutely normal
coronary arteries.
Methods Ninety-one patients (34 females/57 males; mean
age 5013 years, range 2478 years) admitted with an
acute myocardial infarction had absolutely normal cor-
onary arteries at the angiogram performed 624 days
(range 115 days) after the myocardial infarction, dened
by smooth contours and no focal reduction (NC). Of the 91
NC patients, 71 were evaluated prospectively, alongside a
systematic search of all aetiological factors reported in the
literature. The NC patients were matched for age, sex, and
the same period of myocardial infarction onset with a
group of 91 patients with coronary artery stenosis (>50%
diameter stenosis) at the angiogram performed 734 days
(range 115 days) after the myocardial infarction (SC).
Results The percent of smokers was similar between the
two groups; higher prevalence rates of coronary heart
disease family history, obesity, hypertension, hyper-
cholesterolaemia and diabetes mellitus were found in SC
(P=0043 to 00001). In NC, coronary spasm was found in
155%, congenital coagulation disorders in 128%, collagen
tissue disorders in 22%, embolization in 22%, and oral
contraceptive use in 11%. Left ventricular ejection fraction
at hospital discharge was higher in NC (60%13%) than
in SC (55%13%, P=004). The mean follow-up was
35 months (range 1100 months). KaplanMeier event-free
survival, with the combined end-point dened as death,
reinfarction, heart failure and stroke was 75% in NC vs 50%
in SC (P<00001). Survival rate was 945% in NC compared
to 92% in SC (ns). Univariate predictors of events in NC
were left ventricular ejection fraction (P=003), age
(P=002), diabetes (P=001), and smoking (P=003). Using
Cox multivariate analysis, independent predictors of long-
term outcome in NC patients were left ventricular ejection
fraction (P=0003) and diabetes (P=0004).
Conclusion Aetiological factors, predominantly coronary
spasm and inherited coagulation disorder, can be detected
in only one third of the patients with myocardial infarction
and absolutely normal coronary angiograms despite a sys-
tematic search in a prospective population. Mortality rates
are similar but morbidity is lower in myocardial infarction
patients with absolutely normal coronary angiography
compared with those with coronary artery stenosis. The
only two independent factors predictive of poor outcome
in myocardial infarction patients with normal coronary
arteries are left ventricular function and diabetes.
(Eur Heart J 2001; 22: 14591465, doi:10.1053/
euhj.2000.2553)
2001 The European Society of Cardiology
Key Words: Myocardial infarction, prognosis, angio-
graphically normal coronaries.
See page 1364 for the Editorial comment on this article
Revision submitted 27 November 2000, and accepted 29 November 2000.
Correspondence: Pr Karl Isaaz, Service de Cardiologie, Ho pital Nord, Centre Hospitalier Universitaire de Saint-Etienne,
42055 Saint-Etienne CEDEX 2, France.
0195-668X/01/221459+07 $35.00/0 2001 The European Society of Cardiology
Introduction
Although acute myocardial infarction is generally
associated with obstructive coronary artery disease,
myocardial infarction with normal epicardial coronary
arteries have also been documented
[122]
. The overall
prevalence rate of myocardial infarction with a normal
coronary angiogram is low, approximately 3%, but
appears to vary with age, with higher rates in young
patients
[57,21]
. Various mechanisms have been hypoth-
esized
[23]
including coronary spasm
[2430]
, acquired
or inherited coagulation disorders
[3137]
, toxic
conditions
[3841]
, embolization
[42]
. There are limited data
in the published literature regarding the long-term
follow-up of large series of patients who suered an
acute myocardial infarction with an absolutely normal
coronary arteriogram. In addition, to our knowledge, a
systematic search of the most frequently reported aetio-
logical factors has not been done prospectively in a large
cohort of patients. The aim of the present study was: (1)
to compare the long-term prognosis of a large cohort
of myocardial infarction patients with an absolutely
normal coronary angiogram with that of myocardial
infarction patients with coronary artery obstructive dis-
ease; 71 patients (78%) out of our total cohort of
patients were studied prospectively and constituted a
prospective arm; (2) to systematically seek aetiological
factors in the prospective arm of the study and (3) to test
whether prognostic factors may be identied within
the group of myocardial infarction patients with an
absolutely normal coronary angiogram.
Methods
Patient population
Patients who were admitted with acute myocardial
infarction to our institution were screened retrospec-
tively from January 1990 to September 1994 and then
prospectively from October 1994 to December 1998. The
diagnosis of myocardial infarction was based on the
triad of chest pain, ECG changes, and raised plasma
enzyme activity. Ninety-one patients (34 females/
57 males; mean age 5013 years, range 2478 years)
were identied as having angiographically absolutely
normal coronary arteries, dened by epicardial vessels,
smooth contours and no focal reduction on the coronary
angiogram, which was performed 624 days (range
115 days) after myocardial infarction onset (NC).
Among these 91 patients, 20 were retrospectively
included and 71 (78%) were prospectively studied.
Patients in the NC group were matched for age and
gender with a group of 91 patients who presented with
an acute myocardial infarction during the same period
but who had coronary artery stenosis dened by >50%
diameter reduction of at least one major epicardial
coronary vessel at the angiogram performed 734 days
(range 1 to 15 days) after the myocardial infarction (SC).
Classication of the patients into the two groups, based
on the analysis of the coronary angiogram, was made
by three independent experienced angiographers. Age,
gender, angiographic left ventricular ejection fraction,
myocardial infarction location, number of vessels dis-
eased in the SC group and risk factors including family
history of coronary artery disease, diabetes, cigarette
smoking, hypertension, obesity, hypercholesterolaemia
were entered into the analysis. Clinical conditions
known to be associated with hypercoagulation, such as
pregnancy, carcinoma, polycythaemia, collagen tis-
sue disorder, oral contraceptive use were sought
systematically.
Detection of inherited coagulation disorders
Inherited coagulation disorders were sought in only two
of the 20 patients of the retrospective arm and in all the
71 patients of the prospective arm. Blood samples were
taken 4 weeks after myocardial infarction. The absence
of an inammatory syndrome was documented by a
normal brinogen level. Quantitative measurements of
protein C, antithrombin III (ATIII), and plasminogen
were performed by colorimetric assay using, respect-
ively, coamatic protein C from chromogenix (Mo lndal,
Sweden), Stachom ATIII automated, and Stachrom
PLG (Diagnostica Stago, Asnie`res, France). Quantita-
tive determination of functional protein S, based on the
inhibition of factor Va, was established using a clotting
assay of protein S (Staclot protein S, Diagnostica
Stago). A clotting assay was used for quantitative deter-
mination of factor XII. The activated protein C (APC)
resistance test was performed as previously described
with an ST 888 instrument (Diagnostica Stago) using the
coatest activated protein C resistance (APCR, factor V
Leiden) test kit from Biogenic. Patients with a ratio <29
were then subjected to factor V genotyping using a
polymerase chain reaction technique.
Provocative testing for coronary spasm
From September 1994 a provocating test using intra-
venous ergonovine maleate 04 mg within 2 min, was
performed prospectively and systematically in all 71
patients with a normal coronary angiogram to identify
coronary artery spasm. The test was considered positive
when at least 70% focal reduction of luminal diameter
was present.
Follow-up
Clinical events were dened as follows: (1) heart failure;
(2) myocardial infarction recurrence; (3) stroke; and (4)
cardiovascular mortality. Clinical evaluation was made
with a combined end-point, dened by at least one
clinical event. Follow-up (by telephone and interviewing
the patients and their family medical doctor) was carried
out in December 1998 by three observers blinded to the
initial status of the patient. Follow-up was accomplished
1460 A. Da Costa et al.
Eur Heart J, Vol. 22, issue 16, August 2001
in 176 of the 182 patients (97%) and three patients were
lost to follow-up in each group.
Statistical analysis
All continuous variables were reported as mean
valueSD. Dierences among groups were assessed by
one-way ANOVA. Univariate analysis was performed
by log rank test, to assess whether clinical variables and
left ventricular function were predictors of cardiac
events. A P value <005 was considered as signicant.
Multivariate Cox analysis incorporating variables with a
P value <005 in the univariate model was performed to
search for independent predictive factors of cardiac
events.
Results
Baseline characteristics of the two groups
Comparison between NC and SC patients regarding
baseline clinical data, risk factors, location of myo-
cardial infarction and left ventricular dysfunction are
presented in Table 1. NC patients did not dier from SC
patients regarding age, gender and smoking. Statistically
signicant higher prevalence rates of coronary
heart disease family history, obesity, hypertension,
hypercholesterolaemia and diabetes mellitus were found
in SC. Angiographic left ventricular ejection fraction at
hospital discharge was higher in NC (60%14%) than
in SC (55%13%, P=004). No dierence was found
between NC and SC regarding myocardial infarction
location.
Aetiological factors in patients with myocardial
infarction and absolutely normal coronary arteries
Aetiological factors of myocardial infarction in NC
patients are summarized in Table 2. In the 71 NC
patients studied prospectively, a coronary spasm was
documented in 155%. Congenital coagulation disorders
were found in nine of 73 patients (123%), with eight
cases observed in the 71 patients (113%) of the prospec-
tive arm. Congenital coagulation disorders were APC
resistance in seven patients, factor XII in one patient
and protein C deciency in one patient. In the total
cohort of the 91 NC patients, we found a collagen
tissue disorder in two patients (22%, one patient with
systemic lupus erythematosus and one patient with
sarcoidis), embolization in two patients (22%) and oral
contraceptive use in one (11%).
Follow-up
The mean follow-up was 35 months (range 1100
months). Table 3 shows the events observed during the
follow-up in each group. Twenty-two events occurred in
the 91 NC patients: heart failure (n=8), myocardial
reinfarction (n=5), stroke (n=5) and cardiovascular
mortality (n=4). Forty four events occurred in the 91 SC
patients (P<00001 vs NC): heart failure (n=19; P=004
vs NC), myocardial reinfarction (n=15; P=002 vs NC),
stroke (n=3, P=09) and cardiovascular mortality (n=7,
P=038). Although the cardiovascular mortality rate
was 76% higher in SC than in NC (8% vs 45%), the
dierence did not reach statistical signicance. Kaplan
Meier event-free survival, with combined end-point
dened by the association of death, reinfarction, heart
Table 1 Comparison of clinical characteristics between
the two groups
NC
(n=91)
SC
(n=91)
P value
Age (years) 4914 5114 ns
Sex (% female) 37% 37% ns
Smoking (%) 60% 63% ns
Hypertension (%) 154% 35% 0003
Diabetes (%) 10% 24% 0017
Obesity (%) 11% 24% 003
Cholesterol (%) 20% 48% <00001
Family history of CAD (%) 15% 27% 004
LVEF (%) 6013 5513 004
% Anterior MI 5934% 549% ns
CAD=coronary artery disease; LVEF=left ventricular ejection
fraction; MI=myocardial infarction; NC=patients with absolutely
normal coronary arteries; SC=patients with obstructive coronary
arteries.
Table 2 Aetiological factors in the group of patients with myocardial infarction and
normal coronary arteries (in each column, the denominator represents the number of
patients in whom the abnormality has been actually sought)
Retrospective arm
(n=20)
Prospective arm
(n=71)
Overall cohort
(n=91)
Coronary spasm ND 11/71 (155%) 11/71 (155%)
Inherited coagulation disorder 1/2 8/71 (1126%) 9/73 (123%)
Embolization 1/20 (5%) 1/71 (14%) 2/91 (22%)
Collagen tissue disorder 1/20 (5%) 1/71 (14%) 2/91 (22%)
Oral contraceptive use 0/20 1/71 (14%) 1/91 (11%)
ND=no data.
MI with a normal angiogram 1461
Eur Heart J, Vol. 22, issue 16, August 2001
failure and stroke was 75% in NC vs 61% in SC
(P=001). Among 11 variables tested including age,
gender, smoking, hypertension, diabetes, obesity, chol-
esterol level, family history of ischaemic heart disease,
left ventricular ejection fraction, myocardial infarction
location, presence of at least one aetiological factor,
univariate analysis found that predictors of cardio-
vascular events in NC were left ventricular ejection
fraction (P=003), age (P=002), diabetes (P=001), and
smoking (P=003). Using Cox multivariate analysis,
independent predictors of long-term outcome were left
ventricular ejection fraction (P=0003) and diabetes
(P=0004).
In the SC group, among 11 variables tested including
age, gender, smoking, hypertension, diabetes, obesity,
cholesterol level, family history of ischaemic heart dis-
ease, left ventricular ejection fraction, myocardial infarc-
tion location, number of vessels diseased, univariate
analysis found that predictors of cardiovascular events
were left ventricular ejection fraction (P=0009) and
hypertension (P=004). Cox multivariate analysis in
SC patients showed that only left ventricular ejection
fraction (P=002) was an independent predictor of
long-term outcome.
Discussion
Our study suggests that aetiological factors, predomi-
nantly coronary spasm and inherited coagulation dis-
order, can be detected in only one third of patients
with myocardial infarction and an absolutely normal
coronary angiogram, despite a systematic search in a
prospective population. Although morbidity in these
patients is lower than in myocardial infarction patients
with coronary artery stenosis, the mortality rate is
similar. In myocardial infarction patients with an
absolutely normal coronary angiogram, the only two
independent prognostic factors are left ventricular
function and diabetes.
There are limited data in the published literature
regarding the long-term follow-up of large series of
patients who suered an acute myocardial infarction
with an absolutely normal coronary arteriogram. In
addition, to our knowledge, a systematic search of the
most frequently reported aetiological factors has not
been done prospectively in a large cohort of patients.
The rst largest cohort, with a long-term follow-up, was
reported by Raymond et al.
[15]
who suggested a 10 year
survival rate in 74 patients with myocardial infarction
and normal coronary arteries. In the retrospective work
by Raymond et al.
[15]
, only 40 of the 74 studied patients
had absolutely normal coronary arteries and, aetiologi-
cal factors were not systematically sought. In terms of
factors predictive of clinical outcome, Raymond et al.
[15]
did not analyse statistics comparing survivors and non-
survivors in the group of patients with a normal cor-
onary angiogram. More recently, out of a total of 8839
patients who had had a history of myocardial infarction,
Zimmerman et al.
[21]
reported a better survival rate at 7
years in the 720 patients with either angiographically
normal coronary arteries or minimal to moderate dis-
ease, including stenosis with a diameter reduction up to
69%, than in the remaining patients with obstructive
coronary artery disease. Zimmerman et al. did not,
however, perform an analysis of either prognostic fac-
tors or aetiological mechanisms within the subgroup of
patients with absolutely normal coronary arteries
[21]
.
Pathophysiology of myocardial infarction
with normal epicardial coronary arteries
Various mechanisms have been suggested to explain the
occurrence of myocardial infarction despite normal epi-
cardial coronary arteries including coronary spasm,
acquired or inherited coagulation disorders, toxic
agents, embolization, connective tissue disease.
Coronary artery spasm has been proposed as a classic
aetiological factor of myocardial infarction with normal
coronary arteries
[2430]
, but the actual prevalence rate
has remained ill-dened due to the lack of ergonovine
tests in large series of patients. In their study, Raymond
et al. found that coronary artery spasm was present in
ve of the 16 patients (31%) in whom an ergonovine
maleate test was performed
[15]
. The same prevalence was
found by Legrand et al.
[7]
and Lindsay and Pichard
[9]
who evaluated, respectively, 18 and nine patients.
According to our results with a systematically performed
ergonovine maleate test in a larger population of
myocardial infarction patients with normal coronary
arteries, the prevalence rate of coronary artery spasm
appears to be lower than that previously reported in
small sample size populations, since we documented a
spasm in only 11 of the tested 71 patients (155%).
Congenital coagulation abnormalities have also been
hypothesized as possible mechanisms of myocardial
infarction with angiographically normal coronary
arteries
[31,3337]
. Owing to the small size of the popu-
lation sample in previous studies, there was no con-
clusive answer
[3336]
. Recently, a multicentre study has
found a higher prevalence rate of factor V Leiden,
a newly described congenital coagulation disorder,
in patients with myocardial infarction and normal
Table 3 Comparison of outcome at long-term follow-up
between patients with absolutely normal coronary arteries
and those with obstructive coronary arteries
NC SC P value
Follow-up (months) 3317 3518 ns
Events
Heart failure 8/88 (91%) 19/88 (22%) 004
Stroke 5/88 (57%) 3/88 (34%) ns
Reinfarction 5/88 (57%) 15/88 (17%) 002
Cardiovascular mortality 4/88 (45%) 7/88 (8%) ns
Combined end-point 22/88 (25%) 44/88 (50%) <00001
1462 A. Da Costa et al.
Eur Heart J, Vol. 22, issue 16, August 2001
coronary arteries, compared with myocardial infarction
patients and coronary artery stenosis or healthy
subjects
[37]
. In our study, congenital disorders of
coagulation, including activated protein C resistance,
Factor XII and deciency in protein C, were found
in only eight of the 71 patients (113%) in whom
such abnormalities were systematically and prospec-
tively sought. This prevalence rate of congenital co-
agulation abnormalities is lower than that of 182% we
reported previously in a much smaller cohort of younger
patients
[36]
.
Our data show that aetiological factors of myocardial
infarction, with angiographically absolutely normal cor-
onary arteries, are detected in only one third of patients,
even when a systematic search of all causal factors
reported in the published literature is performed. These
results may be partially explained by limitations of the
angiography technique per se, a normal coronary angio-
gram being not necessarily synonymous with structur-
ally normal vessel. This calls for further prospec-
tive studies on the pathophysiological mechanisms of
myocardial infarction.
Long-term prognosis of myocardial
infarction patients with normal coronary
angiogram: is it so good as believed?
Only two large trials have previously been published on
the long-term survival rate of patients with myocardial
infarction and a normal coronary angiogram. The rst
large cohort studied with a long-term follow-up was
reported by Raymond et al.
[15]
, who described ndings
in 74 patients with myocardial infarction and normal
coronary arteries over a mean follow-up period of
105 years. In the retrospective work by Raymond
et al.
[15]
, only 40 of the 74 studied patients had
absolutely normal coronary arteries. In their study,
Raymond et al.
[15]
found a 85% survival rate at
follow-up in patients with a normal coronary arterio-
gram vs 73% in 74 patients with coronary occlusive
disease. More recently, in a total of 8839 patients who
had had a history of myocardial infarction, Zimmerman
et al.
[21]
reported an excellent survival rate of 91% at
7 years in the 720 patients with zero-vessel disease
compared with that of 75% (P<00001) in the remaining
patients with obstructive coronary artery disease. Zero-
vessel disease was dened in the study by Zimmerman
et al.
[21]
as either angiographically normal coronary
arteries or minimal to moderate disease, including
stenosis with a diameter reduction of up to 69%. When
patients with zero-vessel disease were further stratied,
there was no signicant dierence in survival rates
among patients with normal arteries, and minimal or
moderate disease, but the re-infarction rate was higher
in those with minimal and moderate disease (11% and
16% respectively) than in patients with angiographically
normal arteries (5%, P=00002).
In agreement with these two previous studies
[15,21]
, we
have found a high survival rate of 955% at 3 years in
our 91 patients with myocardial infarction and abso-
lutely normal coronary arteries. However, despite this
excellent survival rate, the morbidity of these patients
seems to be signicant since the combined end-points,
including the other major cardiac events (heart failure,
stroke, re-infarction), were observed in 20%. Our results
regarding overall complications are in agreement with
the ndings of Maggi et al.
[20]
who showed, in a smaller
group of 41 patients with myocardial infarction and
completely normal coronary arteries, that the incidence
of complications including angina, re-infarction and
death was 19% after 12 years of follow-up.
Prognostic factors in myocardial infarction
with normal coronary angiogram
By univariate analysis we identied four factors associ-
ated with a poor prognosis in our patients with myo-
cardial infarction and normal coronary arteries: left
ventricular ejection fraction, age, smoking and diabetes.
Multivariate analysis showed that the only two indepen-
dent predictive factors were left ventricular ejection
fraction and diabetes. These two variables have been
demonstrated as major long-term prognostic factors in
patients with myocardial infarction and coronary artery
stenosis
[43,44]
. To our knowledge, our study is the rst to
demonstrate the independent prognostic role of left
ventricular ejection fraction and diabetes in myocardial
infarction patients with absolutely angiographically
normal coronary arteries. Diabetes may play a role in
the prognosis of these patients through its related micro-
vascular dysfunction which may enhance left ventricular
remodelling
[45]
.
Study limitations
Twenty of our 91 studied patients have been evaluated
retrospectively and our study has therefore the inherent
limitations of this design. In particular, several aetiologi-
cal factors, such as coronary artery spasm and coagula-
tion disorders, have been evaluated prospectively in only
71 patients. However, our study provides the largest
prospective series of patients with myocardial infarction
and absolutely normal coronary arteries in whom aetio-
logical factors reported in the literature have been
systematically sought. A larger prospective and multi-
centre study would have been better suited to the
objectives. The other signicant limitation is probably
due to the absence of endovascular analysis with recent
technologies such as coronary angioscopy and intra-
vascular ultrasound, which would allow a better analysis
of the vessel structure and have enabled the limitations
of the angiographic technique to be circumvented.
Conclusions
Patients with myocardial infarction and an absolutely
normal coronary angiogram have a better long-term
MI with a normal angiogram 1463
Eur Heart J, Vol. 22, issue 16, August 2001
prognosis than those with coronary artery stenosis, but
the combined morbidity and mortality are not negligible
in this subset of patients. The only two independent
predictive factors of poor outcome in patients with
myocardial infarction and absolutely normal coronary
arteries are left ventricular function and diabetes.
Despite a systematic search, aetiological factors are
found in only one third of patients and further prospec-
tive studies are needed to improve our understanding
of the pathophysiology of myocardial infarction with
normal coronary arteries.
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Patients with events
(n=22)
Patients without events
(n=66)
P value
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Sex (% female) 41% 20% ns
Smoking (%) 64% 56% 0026
Hypertension (%) 23% 15% ns
Diabetes (%) 15% 5% 001
Obesity (%) 23% 9% ns
Cholesterol (%) 18% 21% ns
Family history of CAD (%) 5% 20% ns
% anterior MI 59% 59% ns
Aetiological factor 363% 182% ns
LVEF (%) 5314 6113 003
CAD=coronary artery disease; MI=myocardial infarction; LVEF=left ventricular ejection
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1464 A. Da Costa et al.
Eur Heart J, Vol. 22, issue 16, August 2001
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Eur Heart J, Vol. 22, issue 16, August 2001