a b s t r a c t

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. The 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 inter- vention due to non-ST-elevation MI (NSTEMI).

Results: Of 4311 consecutive patients with MI, 272 patients (6.3%) did not show significant coronary artery stenosis (group I) and were compared with 253 NSTEMI patients (group II). Younger age (61.9 +- 14.0 vs 65.4 +- 12.0 years; P = .003), female sex (49.3% vs 28.9%; P b .001), less severe anginal symptoms (Canadian Cardiovascular Society class III/IV 41.9% vs 49.8%; P = .05), lower level of myocardial necrosis marker (1.9 +- 6.7 vs 27.4 +- 68.7 ng/mL [troponin], 3.3 +- 4 vs 14.2 +- 20 mmol/L [creatine kinase]; P b .001 for both), and higher left ventricular ejection fraction (58.7% +- 12.6% vs 48.1% +- 12.4%; P b .01) were 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% vs 14.3%; and 2.9% vs 10.1%; P b .01, for both). Event-free survival was more frequent in group I patients (58.4% vs 28.8%; P b .0001) and inversely related to the troponin level.

Conclusions: Absence of significant coronary stenosis accounts for a minority of patients presenting with MI and is associated with a better outcome compared to patients with NSTEMI, and the prognosis is inversely related to the troponin level.

(C) 2014

Introduction

In patients presenting with acute coronary syndrome (ACS), 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 signif- icant coronary artery stenosis at coronary angiography. Nevertheless, those patients are not without risk, and a significant morbidity and mortality are associated with this condition [2,3].

The aim of this study is to provide further information and under- standing of the clinical characteristics and outcome of patients with ACS without critical stenosis and comparing those with a consecutive se- ries of patients with ACS requiring percutaneous coronary intervention.

* Corresponding author. Cardiology Clinic, Zentralklinik Bad Berka, Robert-Koch-Allee 9, 99437 Bad Berka, Germany. Tel.: +49 36458 51201.

E-mail address: [email protected] (M.-A. Ohlow).

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 (b 12 hours) onset of chest pain and elevation of tro- ponin I, creatine kinase, or both. All patients underwent cardiac catheteriza- tion 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 infarc- tion (MI) were then classified into ST-segment elevation MI (STEMI) and non-STEMI (NSTEMI).

Exclusion criteria were as follows:

evidence of bundle-branch block or pacemaker rhythm;

renal failure, defined as decrease of the glomerular filtration rate less than 30 mL/min or as a new or permanent requirement for hemodialysis-which could interfere with measurement of troponin I [4];

http://dx.doi.org/10.1016/j.ajem.2014.10.048

0735-6757/(C) 2014

sepsis or other infectious disease (clinical signs: fever N 38?C or C- reactive protein N 100 mg/L); and

pulmonary embolism (diagnosed by Pathologic findings at Computed tomographic scans of the lungs in patients with elevated D-dimer levels).

The thresholds used to define positive tests were greater than

0.1 ng/mL for troponin I and greater than 0.3 ng/mL for D-dimers, which was the upper normal limit in our laboratory during the study period.

Electrocardiographic analysis

All Electrocardiograms were analyzed retrospectively by an independent observer, who recorded ST-segment depression, Q waves, and T-wave inversion.

Cardiac catheterization

All angiograms recorded after intracoronary application of nitrates were analyzed retrospectively by an independent investigator. Nonsig- nificant coronary artery stenosis was defined by the presence of less than 50% stenosis in any vessel as assessed by visual estimation of the investigator [3]. Five patients underwent percutaneous coronary inter- vention during the index hospitalization and were excluded from the analysis. The comparison group (group II) was made of every 10th pa- tients undergoing percutaneous coronary intervention due to NSTEMI. Furthermore, group I patients were divided into 2 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 appli- cation of nitrates, respectively.

Takotsubo-like left ventricular cardiomyopathy was defined as hypokinesis or akinesis of the mid to apex region of the left ventricle asso- ciated with increased contractility of the base, whenever this extended over a territory supplied by more than one coronary artery [5].

Follow-up

follow-up data were 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 MI or as those requiring reintervention or readmission to the hospital. The cause of death was subclassified as cardiac or noncardiac.

Statistics

Categorical variables are presented as numbers and percentages. Continuous variables are summarized as mean and SD or median, first and third interquartile ranges, depending on normality of distribution. Comparisons for categorical variables were made with ?² or Fisher exact test, as appropriate. The t test or the Wilcoxon-Mann-Whitney test was 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, recurrent angina, and repeat revascularization) are presented with the Kaplan-Meier method. A 2-sided probability value of P b .05 was considered to be statistically significant.

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 patients (93.7%) were excluded due to STEMI (1249 patients, 30.9%) and NSTEMI (2499 patients, 61.9%) diagnosis. An additional 291 patients (7.2%) have been excluded because Troponin elevation was related to noncoronary cardiac disease or noncardiac disease or other excluding factors were present (Table 1).

During the study period, 272 patients (6.3%) with ACS did not show a critical stenosis of any coronary artery. Patients without significant coro- nary stenosis were younger, more often female, and had less severe an- ginal symptoms at presentation, and the history was more frequently negative for previous MI (Table 2 provides relevant clinical information).

Laboratory values

The mean troponin (1.9 +- 5.6 vs 27.41 +- 68.7 ng/mL) and creatine

kinase (4.0 +- 6.5 vs 14.24 +- 19.5 mmol/L) value was significantly higher in group II (P = .001 for both). White cell count (9.51 +- 3.8 x 10³/uL vs 12.4 +- 5.3 x 10³/uL) and hemoglobin level (8.6 +- 1 vs 14.2 +- 1.5 mmol/L) were also higher (P = .03, for both) in patients with significant coronary artery stenosis (Table 3).

Electrocardiographic analysis

Abnormal ECG patterns were significantly more frequent in group II patients: ST-segment depressions (63% vs 17.6%; P b .001), T-wave inversions (66.8% vs 31.1%; P b .001), and Q waves (56.9% vs 2.9%;

P .001) (Table 4).

Table 1

Diagnoses in patients with ACS but without significant coronary artery stenosis

	n	%
No detectable cause (study group)	272	48.3
Myocarditis/inflammatory cardiomyopathy	78	13.9
Pulmonary diseases	41	7.3
Pulmonary embolism Chronic obstructive pulmonary disease + Right heart failure	23 7	4.1 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
Portopulmonary hypertension	2	0.4
Non-small cell Lung cancer	1	0.2
Hypertension related	39	6.9
Takotsubo 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
Sinoatrial block	3	0.5
Atrioventricular 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 d before	1	0.2
Cholecystitis	1	0.2
Pancreatitis	1	0.2
Aortic aneurysm	1	0.2
Hypoglycemia	1	0.2

Table 2

Baseline characteristics

Table 4

Angiographic and ECG characteristics

	Group I (n = 272)	Group II (n = 253)	P		Group I Group II P
Mean age (y)	61.9 +- 14.0	65.4 +- 12.0	b.01		(n = 272) (n = 253)
Range (y)	19-91	36-87			Angiographic characteristics
Sex (male)	138 (50.7%)	180 (71.1%)	b.01		Left ventricular ejection fraction (%)
Prior MI	16 (5.5%)	35 (13.8%)	b.01	Mean		58.7 +- 12.6	48.1 +- 12.4	b.01
Angina pectoris, CCS class III-IV	114 (41.9%)	126 (49.8%)	.05	Range		10-80	10-75
Diabetes mellitus	76 (27.9%)	73 (29.1%)	.8	Regional wall motion abnormalities		66 (24.7%)	171 (67.7%)	b.01
Hypertension	204 (75 %)	173 (68.9%)	.1	No visible atherosclerosis		144 (52.9%)	NA
Hyperlipidemia	119 (43.7%)	76 (30.3%)	b.01	“Non-significant” atherosclerosis		128 (47.1%)	NA
Persistent smoker	62 (22.8%)	70 (28.2%)	.2 (1%-49% diameter stenosis)

Atrial fibrillation 43 (15.8%) 52 (20.6%) .2

Abbreviations: AMI, acute MI; CCS, Canadian Cardiovascular Society. Bold P values means that this is a significant value.

No. of diseased vessels (>=50% diameter stenosis)

3.3. Angiographic analysis	PCI during index hospitalization	0 (0%)	193 (76.3%)	b.01
	CABG during index hospitalization	0 (0%)	60 (23.7%)	b.01
Left ventricular ejection fraction was significantly higher in group I ECG alterations ST-segment depression 48 (17.6%) 160 (63%) b.001

compared with group II (58.7 +- 12.6 vs 48.12 +- 12.4; P = .009). Analysis of regional wall motion abnormalities showed significantly more abnormalities in group II patients (24.7% vs 67.7%; P b .001) (Table 4). There was no angiographic evidence of thrombus, ulcer, or vasospasm in any group I patients.

1-vessel disease	NA	101 (40%)
2-vessel disease	NA	96 (37.9%)
3-vessel disease	NA	56 (22.1%)

3.4. Follow-up data

Clinical follow-up was available for 204 (75%) of 272 group I patients and 189 (75%) of 253 group II patients. The mean follow-up duration was 22.3 +- 22.9 months.

As shown in Table 5 and Fig. 1, the rate of adverse events including all-cause and cardiac mortality was significantly lower in group I pa- tients compared with group II patients (28.8% vs 58.4%; P b .0001). Group I patients without any visible atherosclerosis on baseline angio- gram were significantly less likely to have subsequent angina pectoris, rehospitalization, or congestive heart failure during follow-up com- pared with 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.

Fig. 2 shows the Kaplan-Meier event-free survival curve for the 2 study groups stratified by the troponin level (dichotomization into pa- tients 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% vs 35.7%; P = .04). A troponin level above the mean of 27.4 ng/mL did not correlate with worse prognosis in group II.

Discussion

In this study, 6% of patients with acute onset of chest pain and elevat- ed markers of myocardial necrosis did not show significant (>=50%) cor- onary stenosis at angiography. Their prognosis is better compared to

Table 3

Laboratory values

Abbreviations: CABG, Coronary artery bypass grafting; NA, not applicable; PCI, percutane- ous coronary intervention.

T-wave inversions	79 (31.1%)	182 (66.8%)	b.001

Bold P values means that this is a significant value.

patients with NSTEMI undergoing percutaneous coronary intervention, especially when the troponin levels were low.

Incidence

troponin values above the 99th percentile are encountered in 1% to 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 signif- icant coronary disease is found at coronary angiography. However, the phrase “false-positive troponin elevation” should be restricted to ana- lytic (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 noncoronary pathology or extra cardiac disease, such as severe renal dysfunction [6,8-10]. However, in 272 patients (6% of all screened 4311 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 nonspe- cific binding, effect of matrix selection, and lot-to-lot variation [6,11]. Other proposed explanations include transient thrombosis on noncritically 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 corre- late with prognosis, and higher levels are associated with worse out- come also in patients with chest pain and absence of significant coronary artery stenosis at angiography. This finding suggests cau- tion in categorizing this situation as a “false-positive” result, there-

Group I (n = 272)

Group II P

(n = 253)

fore considering this group of patients as a low risk for subsequent cardiovascular events [3]. The incidence of patients presenting

Creatinine (umol/L) 93.3 +- 49.1 97.8 +- 56.8 .3

Glomerular filtration rate (mL/min) 73.2 +- 24.7 67.4 +- 27.6 .4

C-reactive protein (mg/L) 19.2 +- 40.8 19.2 +- 34 .9

White cell count (x10⁹) 9.3 +- 4.2 12.4 +- 5.3 b.01

Troponin I (ng/mL) 1.9 +- 6.7 27.4 +- 68.7 b.01

Creatine kinase (mmol/L) 3.3 +- 4.2 14.2 +- 19.5 b.01

Hemoglobin level (mmol/L) 8.6 +- 1 14.2 +- 1.5 .03

Hematocrit 0.41 +- 0.04 0.47 +- 0.05 .5 Bold P values means that this is a significant value.

with ACS and troponin elevation but without significant coronary artery disease (CAD) varies in the literature. Older publications re- port 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 [13-16].

Table 5

Follow-up data

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. Coro- nary microvascular dysfunction is frequently found in women without significant obstructive CAD [17-19], and coronary erosions on mild cor- onary plaques has also been described to occur more often in women [20]. This might explain troponin release, increased C-reactive protein

Fig. 1. Event-free survival of group I and group II patients during follow-up. Abbreviations:

CI, confidence interval; HR, hazard ratio.

levels, and higher rate of future events even in (female) patients with- out 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 expla- nation of cardiac damage marker elevation. Several studies have sug- gested that troponins may be released from cardiac myocytes in situation other than necrosis. Normal cell turnover might lead to in- crease in troponin, and approximately 50% of cardiac cells are ex- changed during life [21]. Proteolytic troponin degradation produces

Fig. 2. Event-free survival of group I and group II patients during follow-up by troponin levels.

small fragments that can cross an intact cellular membrane and be de- tected in the bloodstream [22]. Induction of a very short (<=15 minutes) 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 troponin release. This has been showed in a rat model, where increase in preload resulted in myocardial stretch and increase in Troponin I levels, independent of ischemia [24]. In formation and release of membranous blebs, active secretion of vesi- cles (blebs) has been hypothesized to be a mechanism to enable tropo- nin to be released from cardiac cells. Cultured cardiac myocytes have been shown to develop blebs during anoxia and to release cytosolic en- zymes like troponin without undergoing necrosis [25].

Although several clinical, ECG, and laboratory parameters differed sig- nificantly between the 2 groups, it seems to be impossible to identify a pa- tient subgroup in which clinical presentation obviated the need for coronary angiography. Attempts were made to reliably predict the prob- ability of insignificant CAD before angiography. Roe et al [26] proposed a simple nomogram based on 15 clinical and ECG parameters. The sum of these 15 parameters represents the probability that a given patient has in- significant CAD. However, this model was never prospectively evaluated.

Clinical outcome

As expected, the prognosis of patients with ACS undergoing angio- plasty due to significant coronary artery stenosis is worse than in pa- tients 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 obstruc- tion. 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]. Interesting- ly, higher levels of cardiac troponin (N 1.9 ng/mL at admission) are asso- ciated with a worse prognosis in patients with troponin-positive chest pain and absence significant coronary obstruction. Taking this into ac- count, troponin-positive ACS without relevant coronary artery stenosis does not seem to be a Benign condition and may warrant a more aggres- sive medical therapy in such patients. Whether a treatment similar to ACS with relevant coronary artery stenosis (eg, dual platelet inhibition for 12 months and statin medication) can significantly reduce adverse events during follow-up needs to be investigated in further studies.

Limitations

This study was a single-center analysis, which was nonrandomized and retrospective. Troponin data were available at baseline only. The de- gree of coronary stenosis was visually assessed by the interventionalist, and accurate assessment of underlying atherosclerosis in 50% stenosis is limited. Finally, loss of patients at follow-up might have influenced the re- sults of the study.

Conclusion

Approximately 6% of all patients admitted for acute onset of chest pain and elevated markers of myocardial necrosis do not show signifi- cant (>=50%) coronary stenosis at angiography. The use of several differ- ent clinical variables did not help to differentiate patients with and without significant coronary stenosis. The Composite outcome (cardiac death, reinfarction, and rehospitalization) of patients undergoing angio- plasty due to coronary artery disease is worse than that of patients with- out significant coronary stenosis and inversely related to troponin levels. Nonetheless, this latter group is associated with significant

morbidity/mortality, higher troponin levels at admission (N 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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