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(Chest. 2000;117:333-338.)
© 2000 American College of Chest Physicians

Characteristics and Prognosis of Myocardial Infarction in Patients With Normal Coronary Arteries*

Peter Ammann, MD; Sabine Marschall, MD; Martin Kraus, MD; Lucius Schmid, MD; Walter Angehrn, MD; Reto Krapf, MD and Hans Rickli, MD

* From the Department of Cardiology (Drs. Ammann, Kraus, Angehrn, and Rickli), the Institute of Clinical Hematology and Chemistry (Dr. Schmid), and Internal Medicine (Dr. Krapf), Kantonsspital, St. Gallen; and Institute of Immunology and Microbiology (Dr. Marschall), St. Gallen, Switzerland.

Correspondence to: Peter Ammann, MD, Department of Cardiology, Triemli Hospital, 8063-Zurich, Switzerland; e-mail address: pammann@swissonline.ch


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Myocardial infarction with angiographically normal coronary arteries (MINC) is a life-threatening event with many open questions for physicians and patients. There are little data concerning the prognosis for patients with MINC.

Design: Retrospective follow-up study.

Setting: Tertiary referral center.

Patients: Patients with MINC were investigated and compared to age- and sex-matched control subjects with myocardial infarction due to coronary artery disease (CAD). The patients were examined clinically using stress exercise and hyperventilation tests. Migraine and Raynaud’s symptoms were determined by means of a standardized questionnaire. Serum lipoproteins; the seroprevalence of cytomegalovirus, Helicobacter pylori, and Chlamydia pneumoniae infections; and the most frequent causes of thrombophilia were assessed.

Measurements and results: From > 4,300 angiographies that were performed between 1989 and 1996, 21 patients with MINC were identified. The mean ± SD patient age at the time of myocardial infarction was 42 ± 7.5 years. When compared to control subjects (n = 21), patients with MINC had fewer risk factors for CAD. In contrast, MINC patients had more frequent febrile reactions prior to myocardial infarction (six patients vs zero patients; p < 0.05), and the migraine score was significantly higher (7.1 ± 6.3 vs 2.2 ± 4.1; p < 0.01). The seroprevalence of antibodies against cytomegalovirus, C pneumoniae, and H pylori tended to be higher in patients with MINC and CAD as compared to matched healthy control subjects. Three patients with MINC vs none with CAD had coagulopathy. During follow-up (53 ± 37 months), no major cardiac event occurred in the MINC group; no patients with MINC vs nine with CAD (p = 0.0001) underwent repeated angiography.

Conclusion: High migraine score and prior febrile infection together with a lower cardiovascular risk profile are compatible with an inflammatory and a vasomotor component in the pathophysiology of the acute coronary event in MINC patients. The prognosis for these patients is excellent.

Key Words: angiography • coronary artery disease • myocardial infarction • syndrome X


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The leading cause of myocardial infarction in patients with coronary artery disease (CAD) is plaque rupture.1 2 3 4 Since the development of coronary angiography, it has been recognized that 1 to 12% of patients may suffer from a myocardial infarction with angiographically normal coronary arteries (MINC).5 Young people are more likely to suffer an MINC than older people.6 7 The etiology of this disease is still unknown, although coronary spasm8 and thrombosis,9 10 platelet dysfunction, and vasospastic syndromes11 12 associated with Raynaud’s phenomenon and migraine headaches9 have been implicated. Recently, an inflammatory response possibly due to chlamydial or other bacterial and viral infections13 14 15 at the site of coronary thrombosis has been proposed as a mechanism in patients with CAD. The importance of such factors in MINC patients has not been evaluated. Therefore, the aim of this study was to assess the prognosis of MINC patients and to compare the clinical characteristics of these patients to patients with CAD. In addition, hematologic variables associated with a thrombophilia, lipids, and seroprevalence of antibodies against Chlamydia pneumoniae, cytomegalovirus (CMV), and Helicobacter pylori were assessed.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients and Subjects
Between 1989 and 1996, > 4,300 diagnostic coronary arteriographies were performed and 2,100 patients had suffered a prior myocardial infarction. Twenty-five patients (1.2%) with normal coronary arteries and regional hypoakinesia were identified. Twenty-three of them had a classical history of myocardial infarction, definite ECG changes, and a diagnostic increase (greater than twofold) in myocardial enzyme activity. In a second review of the angiograms, done independently by two cardiologists, all of them had angiographically normal coronary arteries without any evidence of endoluminal irregularity. Two patients could not be included in the study because one died in an accident and the other left the country. In our catheter laboratory registry, we identified an age- and sex-matched control group with prior myocardial infarction due to CAD and comparable regional wall motion abnormality. Concerning the seroprevalence studies, a third group of 21 age- and sex-matched healthy blood donors was investigated.

Clinical Investigations
After reviewing the medical records of hospitalization due to myocardial infarction, all patients gave their informed consent for the study. They were asked about angina pectoris before and after the infarction; repeat hospitalizations due to chest pain; new coronary angiographies, or other interventions; febrile infections shortly before infarction; risk factors for CAD (smoking, arterial hypertension, hypercholesterolemia, positive family history, and diabetes mellitus); cocaine abuse; use of sympathomimetics; hormonal contraception; body mass index (BMI); fitness for work; and current medication. Migraine and Raynaud’s symptoms were evaluated by means of a standardized questionnaire in which neither condition was mentioned by name (Table 1 ). A scoring system was established with points assigned for affirmative responses. Migraine was arbitrarily diagnosed if the score totaled >= 7, and Raynaud’s phenomenon was diagnosed if the score totaled >=4.11 Calcium channel blockers and lipid lowering medications were discontinued at least 2 weeks before examination in the control group, and all medication was discontinued in patients with MINC (but not the oral anticoagulation in patients with anterior infarction or poor left ventricular function). In order to provoke vasospasm, we performed a test where the patients hyperventilated for 5 min (until the arterial pH was > 7.6) and ECG was continuously monitored for 15 min on a 12-lead ECG (Megacart R/E; Siemens; Solna, Sweden) for ST-segment changes. Patients were asked about chest pain after hyperventilation. After a recovery time of 20 min, a symptom-limited exercise test on a bicycle ergometer (Ergometer 840; Siemens) was performed with stepwise rise in load every 2 min from 25 to 50 W, depending on expected work capacity. ECG and BP were monitored continuously.


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  		Table 1.. Questionnaire Used To Evaluate the Prevalence of Migraine and Raynaud’s Phenomenon11

 
Venous blood samples were collected for assessment of thrombophilia, lipid metabolism, and seroprevalence for H pylori, C pneumoniae, and CMV. H pylori-specific IgG titers were measured using a commercial enzyme-linked immunosorbent assay (Cobas Core Anti-H. pylori EIA Art. 07 3497 7; Roche Diagnostics; Rotkreuz, Switzerland). The recommended cutoff point was 6 IU/mL. C pneumoniae IgG and IgA titers were measured using microimmunofluorescence (Chlamydia IgG and IgA SeroFIA No. 511–01E and 513–01E; Savyon Diagnostics; Ashdad, Israel). Cross-reactions with Chlamydia trachomatis and Chlamydia psittaci were assessed. IgG titers >= 1:256 and IgA titers >= 1:64 were considered as positive. Tests for CMV IgG antibodies were performed using an enzyme-linked immunosorbent assay (Cobas Core CMV IgG EIA Art. 07 3494 2; Roche Diagnostics) and considered positive when >= 1.0 U/mL.

Statistics
Values are expressed as frequencies and means ± SD. Group comparisons were made using an unpaired Student’s t test or Mann Whitney U statistic. A p value of < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The characteristics of the 21 patients available for further study and those of the control group are shown in Table 2 . The groups were well matched for age, gender, incidence of anterior infarction, and left ventricular ejection fraction. Twenty-three of 2,100 patients (1.1%) by our definition had MINC. The median time interval between myocardial infarction and coronary angiography was 32 days (range, 8 to 145 days) in the MINC group and 27 days (range, 5 to 261 days) in the CAD group.


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  		Table 2.. Baseline Clinical Characteristics of MINC and CAD Patients*

 
In MINC patients, angina pectoris before myocardial infarction was less frequent (1.0 vs 0.7; p = 0.05), and febrile infections, mainly of the upper airways up to 2 weeks prior to infarction, were more frequent (6.0 vs 0.0; p < 0.05). MINC patients less frequently had a history of hypercholesterolemia (9 vs 18; p < 0.01) and hypertension (2 vs 9; p = 0.05), but there was no significant difference concerning other risk factors, such as family history, hormonal substitution, and diabetes.

Patients with MINC had a significantly lower BMI, whereas BP was similar, probably because of drug treatment. In addition, their migraine score was significantly higher. Furthermore, triglycerides, the cholesterol/high-density lipoprotein (HDL) ratio, and apolipoprotein B were all significantly lower, and HDLs and apolipoprotein A1 were higher in patients with MINC. There were no significant differences in lipoprotein(a) and low-density lipoproteins (Table 2) .

The hematologic variables associated with a thrombophilic state were assessed in 18 of 21 patients (3 patients had to be excluded because of oral anticoagulation). Three MINC patients showed coagulopathy (one with combined protein S/plasminogen deficiency, one with anticardiolipin antibody syndrome, and one with a plasminogen deficiency). Overall, no statistically significant differences in the hematologic variables were found (Table 3 ). Antibody titers for CMV, H pylori, and C pneumoniae, and immunfluorescence showed no significant difference between MINC and CAD patients. In contrast, when compared to 21 age- and sex-matched healthy blood donors, the prevalence of antibodies against CMV, C pneumoniae, and H pylori was higher in MINC and CAD patients (Table 4 ).


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  		Table 3.. Hematologic Variables*

 

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  		Table 4.. Prevalence of IgA and IgG Antibodies Against C pneumoniae and IgG Antibodies Against CMV and H pylori*

 
No ECG or clinical evidence for coronary spasm was provoked in either group by hyperventilation.

Follow-up patients with CAD had a higher incidence of rehospitalization because of angina pectoris (11 vs 0; p < 0.0001) and repeated coronary angiography (9 vs 0; p = 0.001) in the follow-up period of at least 7 years (Table 5 ).


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  		Table 5.. Clinical Follow-up at 53 ± 37 Mo*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
One to 12% of individuals with myocardial infarction who undergo coronary angiography are found to have angiographically normal coronary arteries.5 This wide range can be explained by differing definitions of angiographically normal arteries: "without any endoluminal irregularity" and "no significant stenosis (eg, stenosis < 30%)."16 We defined MINC patients as having no detectable endoluminal irregularities. Using this restrictive definition, 1.1% of patients with myocardial infarction fell into this category. Ten of 21 patients in the MINC group and 11 of 21 patients in the CAD group received fibrinolytic therapy. The long duration between the onset of symptoms and hospitalization was the most common exclusion criteria for fibrinolytic therapy. In the 11 patients of the MINC group without fibrinolytic therapy, spontaneous reperfusion of the infarct-related vessel must be postulated. In patients with CAD, the patency rate of the infarct-related vessel was 73% with and 40% without fibrinolytic therapy. The relatively long duration between myocardial infarction and coronary angiography is explained by delayed referral from other hospitals or preceding cardiac rehabilitation after infarction in some patients.

It is recognized that angiography is not the ideal technique to exclude relevant coronary artery wall changes. However, to our knowledge, there are no studies that have investigated MINC patients by means of intravascular ultrasound, which might show wall changes before they become visible on coronary angiography.

Most previous studies of MINC patients have shown that the typical patient is young, without any previous history of chest pain.5 9 The mean age of our patients at the time of myocardial infarction was 42 years, with a high percentage of women (40%); this is similar to the largest series of MINC patients, where the mean age was 43 years and 43% were women.9 Likewise, MINC patients in our study also had significantly less frequent angina prior to myocardial infarction.

Most studies of MINC patients have shown that their cardiovascular risk profile is lower than that of patients with CAD,9 17 whereas others did not find a difference.18 We found statistically significant lower BMI, a lower ratio of cholesterol/HDL levels, and a lower incidence of arterial hypertension in MINC patients compared to patients with CAD. In contrast, we found no difference in smoking or therapeutic hormone replacement.

An endothelial dysfunction with a tendency toward increased vasomotor tone has also been implicated.19 The high migraine score in MINC patients in this and other studies9 indicates a possible pathophysiologic link. However, when using hyperventilation, it was neither possible to show myocardial ischemia in the 12-lead ECG nor to provoke typical chest pain. Testing with ergonovine maleate might be a superior method to provoke artery spasm in this group of patients.9

The fact that smokers show a decreased production of nitric oxide,20 which partly mediates endothelium-dependent vasodilation, and because most of the patients with MINC are smokers, a pathophysiologic link may seem plausible.21 22 23 24 However, 76% of our MINC patients and 67% of our CAD patients were smokers at time of infarction. Thus, this factor alone is not a major discriminator between both groups. Cocaine abuse has been shown to cause myocardial infarction in some patients with normal coronary arteries.25 26 None of our patients reported cocaine abuse prior to myocardial infarction, but analysis of cocaine in urine samples was performed in one patient only.

Three out of 21 patients (16.6%) had biochemical evidence of increased thrombogenicity. This is in contrast to other reports.18 27 The number of patients tested is too small to generally recommend extensive laboratory screening in these patients.

An interesting finding in our study was the significantly higher number of patients with febrile infections mainly of the upper airways, within 2 weeks prior to infarction in the MINC group. This finding raises new questions of etiology in some MINC patients. Is there a coronary thrombosis and/or a rupture of an angiographically overworked plaque triggered by systemic inflammation itself or by specific infective components? Recent studies have suggested a possible association of C pneumoniae, CMV, and H pylori infections in the etiology of acute coronary syndromes in patients with CAD. Endothelial injury due to circulating endotoxin, autoimmunity with cross-reactivity of bacterial antigens and endothelial cells are discussed as possible underlying mechanisms.15 Our finding of higher incidence of IgA titers against C pneumoniae as compared to healthy blood donors would be compatible with an inflammatory component of acute myocardial infarction. In this context, it is furthermore tempting to speculate that the higher incidence of febrile infections in our MINC patients might be causally related to their coronary event. However, we found no difference in antibody titers to CMV and H pylori between MINC and CAD patients. Nevertheless, no repeat titer determinations were done and a potential difference with regard to infections with these agents cannot be dismissed.

The febrile episodes before infarction in our MINC patients raise the question as to whether myocarditis might have mimicked acute myocardial infarction in some patients. Myocardial infarction was diagnosed in our patients with MINC by definite ECG changes, a diagnostic increase in myocardial enzyme activity, and, most importantly, regional wall motion abnormality on ventriculography.

The prognosis for MINC patients is excellent. During follow-up at a mean of 5.3 years after infarction, MINC patients had a very good exercise capacity. No one had a major adverse cardiac event or required repeat coronary angiography.


   Footnotes
 
Abbreviations: BMI = body mass index; CAD = coronary artery disease; CMV = cytomegalovirus; HDL = high-density lipoprotein; MINC = myocardial infarction with angiographically normal coronary arteries

Received for publication January 26, 1999. Accepted for publication June 29, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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