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Acute coronary syndrome without critical epicardial coronary disease: preva-lence, characteristics, and outcome

Marc-Alexander Ohlow MD, PhD, Vincent Wong, Michele Brunelli,Hubertus von Korn MD, Ahmed Farah MD, Nedim Memisevic MD, StefanRichter MD, Ketevan Tukhiashvili, Bernward Lauer MD, PhD

PII: S0735-6757(14)00787-6DOI: doi: 10.1016/j.ajem.2014.10.048Reference: YAJEM 54599

To appear in: American Journal of Emergency Medicine

Received date: 2 July 2014Revised date: 24 October 2014Accepted date: 29 October 2014

Please cite this article as: Ohlow Marc-Alexander, Wong Vincent, Brunelli Michele, vonKorn Hubertus, Farah Ahmed, Memisevic Nedim, Richter Stefan, Tukhiashvili Ketevan,Lauer Bernward, Acute coronary syndrome without critical epicardial coronary disease:prevalence, characteristics, and outcome, American Journal of Emergency Medicine (2014),doi: 10.1016/j.ajem.2014.10.048

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Acute coronary syndrome without critical epicardial coronary disease:

prevalence, characteristics, and outcome

Ohlow1, Marc-Alexander (corresponding author), MD, PhD: Cardiology Clinic, Zentralklinik Bad

Berka, Robert-Koch-Allee 9, 99437 Bad Berka, Germany

Phone: 0049 36458 51201; e-mail: marc.ohlow@zentralklinik.de

Wong1, Vincent: Cardiology Clinic, Zentralklinik Bad Berka, Germany

Brunelli1, Michele: Cardiology Clinic, Zentralklinik Bad Berka

von Korn1, Hubertus, MD: Medizinische Klinik I, Krankenhaus Hetzelstift, Neustadt/Weinstrasse,

Germany

Farah1, Ahmed, MD: Cardiology Clinic, Zentralklinik Bad Berka, GermanyMemisevic

1, Nedim, MD:

Cardiology Clinic, Zentralklinik Bad Berka, Germany

Richter1, Stefan, MD: Cardiology Clinic, Zentralklinik Bad Berka, Germany

Tukhiashvili1, Ketevan: Cardiology Clinic, Zentralklinik Bad Berka, Germany

Lauer1, Bernward, MD, PhD: Cardiology Clinic, Zentralklinik Bad Berka, Germany

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Background: Absence of significant epicardial coronary artery stenosis in patients with acute onset

of chest pain and elevation of myocardial necrosis markers is occasionally observed. Aim of this

study was to retrospectively analyze the clinical characteristics and the outcome of such patients.

Methods: All patients with myocardial infarction (MI) but without significant coronary artery

stenosis (≥50%) on angiography from May 2002 to April 2011 were compared with patients

undergoing percutaneous coronary intervention due to Non-ST-Elevation Myocardial Infarction

(NSTEMI).

Results: Out of 4.311 consecutive patients with MI, 272 (6.3%) patients did not show significant

coronary artery stenosis (Group I), and were compared with 253 NSTEMI patients (Group II).

Younger age (61.9±14.0 versus 65.4±12.0 years; p=0.003), female gender (49.3% versus 28.9%;

p<0.001), less severe anginal symptoms (CCS class III/IV 41.9% versus 49.8%; p=0.05), lower

level of myocardial necrosis marker (1.9±6.7 ng/ml versus 27.4±68.7ng/ml [troponin], 3.3±4

mmol/l versus 14.2±20 mmol/l [creatine kinase]; p<0.001 for both), and higher left ventricular

ejection fraction (58.7±12.6% versus 48.1±12.4%; p<0.01) was associated with Group I patients. At

a mean follow-up of 22.3±22.9 months, all-cause and cardiac mortality was lower in Group I

patients (4.9% versus 14.3%; and 2.9% versus 10.1%; p<0.01, for both). Event-free survival was

more frequent in Group I patients (58.4% versus 28.8%; p<0.0001) and inversely related to the

troponin level.

Conclusions: Absence of significant coronary stenosis accounts for a minority of patients

presenting with MI, is associated with a better outcome compared to patients with NSTEMI, and the

prognosis is inversely related to the troponin level.

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INTRODUCTION

In patients presenting with acute coronary syndrome, an elevated level of cardiac troponins

(suggestive of myocardial necrosis) is a well-known risk factor for fatal events [1,2].

However, a minority of patients presenting with acute onset of chest pain and elevated level of cardiac

necrosis markers will not have significant coronary artery stenosis at coronary angiography. Nevertheless,

those patients are not without risk and a significant morbidity and mortality is associated with this condition

[2,3].

Aim of this study is to provide further information and understanding of the clinical characteristics and

outcome of patients with ACS without critical stenosis, and comparing those with a consecutive series of

patients with ACS requiring percutaneous coronary intervention.

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2. PATIENTS AND METHODS

Using our hospital's database, we retrospectively analyzed the records of all consecutive patients

who had been admitted from May 2002 to April 2011 with acute (<12 h) onset of chest pain and

elevation of troponin I, creatine kinase, or both. All patients underwent cardiac catheterization

within 12 hours of hospital admission. The study protocol conforms to the ethical guidelines of the

1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research

committee.

Patients without significant coronary stenosis constitute the study population and were assigned to

Group I. Patients with myocardial infarction were then classified into ST-segment Elevation

Myocardial Infarction (STEMI) and Non-ST-Elevation Myocardial Infarction (NSTEMI).

Exclusion criteria were:

1) evidence of bundle-branch block or pacemaker rhythm;

2) renal failure, defined as decrease of the glomerular filtration rate below 30 ml/min or as a

new or permanent requirement for hemodialysis—which could interfere with measurement

of troponin I [4];

3) sepsis or other infectious disease (clinical signs: fever >38 °C or C-reactive protein >100

mg/l);

4) pulmonary embolism (diagnosed by pathological findings at computed tomographic

scans of the lungs in patients with elevated D-dimer levels).

The thresholds used to define positive tests were >0.1 ng/ml for troponin I and >0.3 ng/ml for D-

dimers, which was the upper normal limit in our laboratory during the study period.

2.1. Electrocardiographic Analysis

All ECGs were analyzed retrospectively by an independent observer, who recorded ST-segment

depression, Q waves, and T-wave inversion.

2.2. Cardiac Catheterization

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All angiograms recorded after intracoronary application of nitrates were analyzed retrospectively by

an independent investigator. Non-significant coronary artery stenosis was defined by the presence

of <50% stenosis in any vessel as assessed by visual estimation of the investigator [3]. Five patients

underwent percutaneous coronary intervention during the index hospitalization and were excluded

from the analysis. The comparison group (Group II) was made of every 10th patients undergoing

percutaneous coronary intervention due to NSTEMI. Furthermore, Group I patients were divided

into two subgroups: (1) patients without any visible atherosclerosis, and (2) patients with some

degree of atherosclerosis (1%-49% diameter stenosis).

Intraluminal thrombus, ulcer, and vasospasm were defined as a filling defect separated from the

adjacent vascular wall, a breakdown of the plaque surface, and a stenosis that could be reversed by

the application of nitrates, respectively.

Takotsubo-like left ventricular cardiomyopathy was defined as hypokinesis or akinesis of the mid to

apex region of the left ventricle associated with increased contractility of the base, whenever this

extended over a territory supplied by more than one coronary artery [5].

2.3. Follow-Up

Follow-up data was obtained by reviewing the patient's hospital charts, conducting standardized

telephone interviews, contacting the patient's physician if necessary, or conducting periodic

outpatient visits. Anginal status was noted, and adverse events were identified as myocardial

infarction or as those requiring re-intervention or readmission to the hospital. The cause of death

was subclassified as cardiac or non-cardiac.

2.4. Statistics

Categorical variables are presented as numbers and percentages. Continuous variables are

summarized as mean and standard deviation or median, first and third interquartile ranges,

depending on normality of distribution. Comparisons for categorical variables were made with χ2 or

Fisher’s exact test, as appropriate. The t-test or the Wilcoxon-Mann-Whitney test were used to

compare continuous variables, as appropriate. The log-rank test (Mantel-Cox) statistic was used to

compare event rates. Clinical outcomes (combined end point: death, congestive heart failure,

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recurrent angina, and repeat revascularization) are presented with the Kaplan-Meier method. A

two-sided probability value of p <0.05 was considered to be statistically significant.

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3. RESULTS

Between May 2002 and April 2011, 4311 patients were admitted at our institution with recent onset

of chest pain and a serum elevation of troponin I and/or creatine kinase.

Of those, 4039 (93.7%) patients were excluded due to STEMI (1249 patients, 30.9%), and NSTEMI

(2499 patients, 61.9%) diagnosis. An additional 291 (7.2%) patients have been excluded because

troponin elevation was related to non-coronary cardiac disease, non-cardiac disease or other

excluding factors were present (Table 1).

Table 1: Diagnoses in patients with acute coronary syndrome but without significant coronary artery stenoses

(n=563)

During the study period, 272 (6.3%) patients with ACS did not show a critical stenosis of any

coronary artery. Patients without significant coronary stenosis were younger, more often female,

had less severe anginal symptoms at presentation, and the history was more frequently negative for

previous myocardial infarction (Table 2 provides relevant clinical information).

Table 2: Baseline characteristics

3.1. Laboratory Values

The mean troponin (1.9±5.6 ng/ml versus 27.41±68.7 ng/ml) and creatine kinase (4.0±6.5 mmol/l

versus 14.24±19.5 mmol/l) value was significantly higher in Group II (p=0.001 for both). White cell

count (9.51±3.8 x 103/µl versus 12.4±5.3 x 10

3/µl) and hemoglobin level (8.6±1 mmol/l versus

14.2±1.5 mmol/l) were also higher (p=0.03, for both) in patients with significant coronary artery

stenosis (Table 3).

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Table 3: Laboratory values

3.2. Electrocardiographic Analysis

Abnormal ECG patterns were significantly more frequent in Group II patients: ST-segment

depressions (63% versus 17.6%; p<0.001), T-wave inversions (66.8% versus 31.1%; p<0.001), and

Q waves (56.9% versus 2.9%; p<0.001); Table 4.

3.3. Angiographic Analysis

Left ventricular ejection fraction was significantly higher in Group I compared with Group II

(58.7±12.6 versus 48.12±12.4; p=0.009). Analysis of regional wall-motion abnormalities showed

significantly more abnormalities in Group II patients (24.7% versus 67.7%; p<0.001); Table 4.

There was no angiographic evidence of thrombus, ulcer, or vasospasm in any Group I patients.

Table 4: Angiographic and electrocardiographic characteristics

3.4. Follow-Up Data

Clinical follow-up was available for 204/272 Group I patients (75%) and 189/253 (75%) Group II

patients. The mean follow-up duration was 22.3±22.9 months.

As shown in Table 5 and Figure 1 the rate of adverse events including all cause and cardiac

mortality was significantly lower in Group I patients compared with Group II patients (28.8%

versus 58.4%; p<0.0001). Group I patients without any visible atherosclerosis on baseline

angiogram were significantly less likely to have subsequent angina pectoris, re-hospitalization, or

congestive heart failure during follow-up compared to Group I patients with “non-significant”

atherosclerosis. However, the total number of deaths was to low to demonstrate this for all cause

and cardiac mortality, respectively.

Figure 2 shows the Kaplan-Meier event-free survival curve for the two study groups stratified by

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the troponin level (dichotomization into patients below and above the mean troponin value of the

respective group). A troponin level below the mean troponin value of 1.9 ng/ml was associated with

a significantly lower event-rate during follow-up among Group I patients (24.9% versus 35.7%;

p=0.04). A troponin level above the mean of 27.4 ng/ml did not correlate with worse prognosis in

Group II.

Table 5: Follow-up data

Figure 1: Event-free survival of Group I and Group II patients during follow-up (CI: confidence

interval, HR: hazard ratio)

Figure 2: Event-free survival of Group I and Group II patients during follow-up by troponin levels

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4. DISCUSSION

In this study, 6% of patients with acute onset of chest pain and elevated markers of myocardial

necrosis did not show significant (≥50%) coronary stenosis at angiography. Their prognosis is better

compared to patients with NSTEMI undergoing percutaneous coronary intervention, especially

when the troponin levels were low.

4.1. Incidence

Troponin values above the 99th

percentile are encountered in 1-3% of a healthy population [6]. A

troponin increase reflects acute or chronic myocardial damage but is not exclusive to ACS, and this

can lead to difficulties in the interpretation of the result. The term false-positive has been used to

describe the situation in which acute onset of chest pain is associated with an elevated troponin

level, but no significant coronary disease is found at coronary angiography. However, the phrase

“false-positive troponin elevation” should be restricted to analytic (technical) issues and the term

“non AMI related troponin elevation” should be used until the true ethiopathogenesis in an

individual patient is recognized [7]. This might be related to several cardiac but non-coronary

pathology or extra cardiac disease, such as severe renal dysfunction [6,8-10]. However, in 272

patients (6% of all screened 4,311 patients) elevated troponin levels could not be explained despite

thorough clinical examination. Some of the cases might be related to heterophilic antibodies [6], or

several analytical issues including non-specific binding, effect of matrix selection, and lot-to-lot

variation [6,11]. Other proposed explanations include transient thrombosis on non-critically

obstructive plaque [12], epicardial coronary vasospasm [12], or abnormalities in microvascular

resistance of the small coronary arteries [12]. Irrespective of the precise mechanism leading to

troponin elevation, this study demonstrates that cardiac damage markers correlate with prognosis,

and higher levels are associated with worse outcome also in patients with chest pain and absence of

significant coronary artery stenosis at angiography. This finding suggest caution in categorizing this

situation as a “false-positive” result, therefore considering this group of patients as a low-risk for

subsequent cardiovascular events [3]. The incidence of patients presenting with ACS and troponin

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elevation but without significant CAD varies in the literature. Older publications report 11% to 19%

[10,11], whereas more recent publications report normal coronary arteries in ACS and troponin

positive patients in 6% to 9% [2,3], which is well comparable to our results. However, the

widespread use of high-sensitive troponin might change the incidence of ACS plus elevated

troponin but without CAD in the future [14-16].

4.2. Clinical presentation, laboratory values and ECG alterations

Patients presenting without significant coronary stenosis, but with chest pain and elevated troponin

level were younger, had less severe angina symptoms, and more likely to be women, compared to

patients undergoing angioplasty due to significant coronary obstruction. Coronary microvascular

dysfunction is frequently found in women without significant obstructive CAD [17-19], and

coronary erosions on mild coronary plaques has also been described to occur more often in women

[20]. This might explain troponin release, increased CRP levels, and higher rate of future events

even in (female) patients without significant coronary stenosis. However, the absence of correlation

between sex and outcome in our study seems supporting the idea that microvascular dysfunction

and coronary erosion are not the only explanation of cardiac damage marker elevation. Several

studies have suggested that troponins may be released from cardiac myocytes in situation other than

necrosis. Normal cell turnover might lead to increase in troponin, and approximately 50% of

cardiac cells are exchanged during life [21]. Proteolytic troponin degradation produces small

fragments that can cross an intact cellular membrane and be detected in the blood stream [22].

Induction of a very short (≤15 min) and mild ischemia generates cellular release of troponin I

degradation products [23]. Increased cellular wall permeability, due to myocardial stretch, is

another potential cause of of troponin release. This has been showed in a rat model, where increase

in pre-load resulted in myocardial stretch and increase in troponin I levels, independent of ischemia

[24]. (4) Formation and release of membraneous blebs: Active secretion of vesicles (blebs) has

been hypothesized to be a mechanism to enable troponin to be released from cardiac cells. Cultured

cardiac myocytes have been shown to develop blebs during anoxia and to release cytosolic enzymes

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like troponin without undergoing necrosis [25].

Although several clinical, electrocardiographic and laboratory parameters differed significantly

between the two groups, it seems to be impossible to identify a patient subgroup in which clinical

presentation obviated the need for coronary angiography. Attempts were made to reliably predict the

probability of insignificant CAD before angiography. Roe and co-workers proposed a simple

nomogram based on 15 clinical and electrocardiographic parameters [26]. The sum of these 15

parameters represents the probability that a given patient has insignificant CAD. However, this

model was never prospectively evaluated.

4.3. Clinical outcome

As expected, the prognosis of patients with ACS undergoing angioplasty due to significant

coronary artery stenosis is worse than in patients with troponin-positive chest pain and absence

significant obstruction (hazard ratio 2.44). However, a significant event-rate of 28.8% over a period

of 86 months was found in patients with troponin-positive chest pain and absence significant

coronary obstruction. This translates in an annual event-rate of 4%, which is higher than the 2.4%

of an a healthy population of comparable age [27]. Interestingly, higher levels of cardiac troponin

(more than 1.9 ng/ml at admission) are associated with a worse prognosis in patients with troponin-

positive chest pain and absence significant coronary obstruction. Taking this into account, troponin-

positive ACS without relevant coronary artery stenosis does not seem to be a benign condition and

may warrant a more aggressive medical therapy in such patients. Whether a treatment similar to

acute coronary syndrome with relevant coronary artery stenosis (e.g. dual platelet inhibition for 12

months, and statin medication) can significantly reduce adverse events during follow-up needs to be

investigated in further studies.

4.4. Limitations

This study was a single center analysis, which was non-randomized and retrospective. Troponin

data was available at baseline only. The degree of coronary stenosis was visually assessed by the

interventionalist, and accurate assessment of underlying atherosclerosis in 50% stenosis is limited.

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Finally, loss of patients at follow-up might have influenced the results of the study.

4.5. Conclusion

Approximately 6% of all patients admitted for acute onset of chest pain and elevated markers of

myocardial necrosis do not show significant (≥50%) coronary stenosis at angiography. The use of

several different clinical variables did not help to differentiate patients with and without significant

coronary stenosis. The composite outcome (cardiac death, re-infarction and re-hospitalization) of

patients undergoing angioplasty due to coronary artery disease is worse than that of patients without

significant coronary stenosis and inversely related to troponin levels. Nonetheless, this latter group

is associated with significant morbidity/mortality, higher troponin levels at admission (>1.9 ng/ml)

are associated with worse prognosis, and the cardiac event free survival is lower than expected for a

population of comparable age.

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Tables

Table 1: Diagnoses in patients with acute coronary syndrome but without significant coronary artery stenosis

n %

No detectable cause (study group) 272 48.3

Myocarditis/inflammatoric cardiomyopathy 78 13.9

Pulmonary diseases 41 7.3

Pulmonary embolism 23 4.1

Chronic obstructive pulmonary disease + right heart failure 7 1.2

Spontaneous pneumothorax 2 0.4

Tension pneumothorax with AV-Block 3 2 0.4

Pneumonia with pericarditis 2 0.4

Acute respiratory distress syndrome 2 0.4

Porto-pulmonary hypertension 2 0.4

Non-small cell lung cancer 1 0.2

Hypertension related 39 6.9

Tako-Tsubo-syndrome 39 6.9

Rhythm disturbances 35 6.2

AV-Block 3 10 1.8

Atrial fibrillation 7 1.2

Coronary embolic events 5 0.9

Tachymyopathy 2 0.4

Ventricular tachycardia 4 0.8

Sinu-atrial-block 3 0.5

Atrio-ventricular nodal re-entry tachycardia 2 0.4

Frequent premature ventricular complexes 1 0.2

Implantable defibrillator discharge 1 0.2

Pericarditis 9 1.6

Worsened heart failure of known dilated cardiomyopathy 9 1.6

Aortic stenosis 8 1.4

Endocarditis 6 1.1

Sepsis 5 0.9

Hypovolemia 4 0.8

Ischemic stroke/transistoric ischemic cerebral event 4 0.8

Analytic error 2 0.4

Ruptured coronary plaque with spontaneous lysis 2 0.4

Borelliosis 1 0.2

Coronary spasm 1 0.2

Hypertrophic obstructive cardiomyopathy 1 0.2

Hyperthyroidism 1 0.2

Amyloidosis 1 0.2

Percutaneous coronary intervention 10 days before 1 0.2

Cholecystitis 1 0.2

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Pancreatitis 1 0.2

Aortic aneurysm 1 0.2

Hypoglycemia 1 0.2

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Table 2: Baseline characteristics

Group I

(n=272)

Group II

(n=253) p-Value

Mean age [years] 61.9±14.0 65.4±12.0 <0.01

Range [years] 19 – 91 36 – 87

Gender [male] 138 (50.7%) 180 (71.1%) <0.01

Prior myocardial infarction 16 (5.5%) 35 (13.8%) <0.01

Angina pectoris, CCS class III-IV 114 (41.9%) 126 (49.8%) 0.05

Diabetes mellitus 76 (27.9%) 73 (29.1%) 0.8

Hypertension 204 (75 %) 173 (68.9%) 0.1

Hyperlipidemia 119 (43.7%) 76 (30.3%) <0.01

Persistent smoker 62 (22.8%) 70 (28.2%) 0.2

Atrial fibrillation 43 (15.8%) 52 (20.6%) 0.2

AMI=acute myocardial infarction; CCS=Canadian Cardiovascular Society

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Table 3: Laboratory values

Group I

(n=272)

Group II

(n=253)

p-Value

Creatinine (µmol/L) 93.3±49.1 97.8±56.8 0.3

Glomerular filtration rate (ml/min) 73.2±24.7 67.4±27.6 0.4

C-reactive Protein (mg/l) 19.2±40.8 19.2±34 0.9

White cell count (x 109) 9.3±4.2 12.4±5.3 <0.01

Troponin I (ng/ml) 1.9±6.7 27.4±68.7 <0.01

Creatin kinase (mmol/l) 3.3±4.2 14.2±19.5 <0.01

Hemoglobin (mmol/l) 8.6±1 14.2±1.5 0.03

Hematocrit 0.41±0.04 0.47±0.05 0.5

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Table 4: Angiographic and electrocardiographic characteristics

Group I

(n=272)

Group II

(n=253) p-Value

Angiografic characteristics

Left ventricular ejection fraction [%]

Mean 58.7±12.6 48.1±12.4

<0.01 Range 10-80 10-75

Regional wall-motion abnormalities 66 (24.7%) 171 (67.7%) <0.01

No visible atherosclerosis 144 (52.9%) na

“non-significant” atherosclerosis (1%-49% diameter stenosis) 128 (47.1%) na

# of diseased vessels (≥50% diameter stenosis)

1-vessel-disease na 101 (40%)

2-vessel-disease na 96 (37.9%)

3-vessel-disease na 56 (22.1%)

PCI during index hospitalization 0 (0%) 193 (76.3%) <0.01

CABG during index hospitalization 0 (0%) 60 (23.7%) <0.01

ECG alterations

ST-segment depression 48 (17.6%) 160 (63%) <0.001

T-wave inversions 79 (31.1%) 182 (66.8%) <0.001

CABG=coronary artery bypass grafting; na=not applicable; PCI=percutaneous coronary intervention

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Table 5: Follow-up data

Group I Group II p-Value

Number of patients in follow-up 204/272 (75%) 189/253 (75%) 0.9

mean follow-up duration (months) 27±25.9 17.5±19.9 <0.01

All cause mortality 10 (4.9%) 27 (14.3%) 0.002

Cardiac death 6 (2.9%) 19 (10.1%) 0.006

Myocardial infarction 2 (1%) 11 (5.8%) <0.01

Recurrent angina pectoris 14 (20.1%) 43 (22.8%) 0.6

Readmission to hospital 28 (13.7%) 94 (49.7%) <0.0001

Congestive heart failure (NYHA II-IV) 22 (10.8%) 40 (21.2%) <0.01

Group I

No visible atherosclerosis

(n=144) “Non-significant”

atherosclerosis (n=128)

Number of patients in follow-up 108 (75%) 96 (75%) 0.9

All cause mortality 4 (3.7%) 6 (6.3%) 0.52

Cardiac death 2 (1.9%) 4 (4.2%) 0.42

Myocardial infarction 0 (0%) 2 (2.1%) 0.22

Recurrent angina pectoris 3 (2.8%) 11 (11.5%) 0.02

Readmission to hospital 9 (8.3%) 19 (19.8%) 0.02

Congestive heart failure (NYHA II-IV) 7 (6.5%) 15 (15.6%) 0.04

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7. LEGENDS

Figure 1: Event-free survival of Group I and Group II patients during follow-up (CI: confidence

interval, HR: hazard ratio)

Figure 2: Event-free survival of Group I and Group II patients during follow-up by troponin levels

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Figure 1

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Figure 2