Usefulness of Neuron-Specific Enolase to Detect Silent Neuronal Ischemia After Percutaneous Coronary Intervention

Usefulness of Neuron-Specific Enolase to Detect Silent Neuronal Ischemia After Percutaneous Coronary Intervention Huseyin Goksuluk, MD*, Sadi Gulec, MD, Ozgur Ulas Ozcan, MD, Menekse Gerede, MD, Veysel Kutay Vurgun, MD, Nil Ozyuncu, MD, and Cetin Erol, MD Increased plasma levels of neuron-specific enolase (NSE) are related to damage of neurons and neuroendocrine cells. We aimed to investigate elevation of NSE after elective percutaneous coronary intervention (PCI) on the prediction of silent cerebral infarct (SCI). Study population consisted of 2 groups of patients. Group 1 included 92 consecutive patients with normal coronary angiograms, whereas group 2 consisted of 89 patients who underwent elective coronary stenting. NSE levels were studied before and 12 hours after the procedure. Elevation of >0.12 mg/L was considered as SCI. Forty-seven of 181 study patients (26%) had SCI after the procedure. NSE elevation was significantly more prevalent in patients with PCI than that of controls. Elevation of NSE was observed in 42% of patients who underwent elective PCI (n [ 37) and 11% of the normal coronary artery group (n [ 10) (p <0.001). The incidence of SCI was higher in active smokers and patients who had history of myocardial infarction (MI) (55% vs 10%, p <0.001 for active smokers and 40% vs 8%, p <0.001 for history of MI, respectively). Multivariate analysis demonstrated history of smoking (odds ratio [OR] 9.9; 95% confidence interval [CI] 3.7 to 26.9; p <0.001) and previous MI (OR 4.4; 95% CI 1.7 to 11.4; p [ 0.01) as independent predictors of SCI. For patients who underwent elective PCI, NSE levels after procedure increases. Invasive coronary procedures have risk of SCIs, even in patients with normal coronary arteries. In conclusion, increased diagnosis of SCIs might improve understanding of their relation with invasive cardiac procedures, facilitate to prevent occurrence of silent microemboli and decrease the risk of adverse neurologic events. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;117:1917e1920)

Neuron-specific enolase (NSE) is an intracytoplasmic glycolytic enzyme found in neurons and neuroendocrine tissues.1 Elevation of NSE in the absence of any clinically apparent stroke or transient ischemic attack, so-called silent cerebral infarcts (SCIs), may be associated with neurologic deficits,2,3 cognitive decline,4,5 psychiatric disorders (i.e., depression),3,6 clinically apparent stroke,7,8 and even increased mortality.7,9 Although rare, PCIs are known to cause cerebral embolic events. However, their role in the genesis of SCIs is not well documented. In the present study, we aim to evaluate the incidence of SCIs, defined as an elevation of NSE after diagnostic coronary angiography and elective coronary stenting. Methods Study population consisted of 2 groups of patients. Group 1 included 92 consecutive patients with normal coronary angiograms (no >50% diameter stenosis in any of Cardiology Department, Ankara University, Ankara, Turkey. Manuscript received December 29, 2015; revised manuscript received and accepted March 16, 2016. See page 1919 for disclosure information. *Corresponding author: Tel: (þ90) 532-548-6123; fax: (þ90) 312-3125251. E-mail address: [email protected] (H. Goksuluk). 0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.03.037

the major coronary artery or their branches); group 2 consisted of 89 patients who underwent elective coronary stenting. Exclusion criteria were (1) baseline NSE elevation, (2) acute coronary syndromes or cardiac surgery within 4 weeks, (3) left ventricular dysfunction (left ventricular ejection fraction <50%), (4) planned use of glycoprotein IIb/IIIa receptor inhibitors, (5) patients with recent cerebrovascular accident, intracranial hemorrhage, and head trauma, (6) central nervous system tumor, (7) degenerative central nervous system disorders, (8) neuroendocrine tumors, and (9) symptomatic peripheral vascular disease. All patients gave written informed consent, and local ethics committee approved the study protocol. All patients (n ¼ 181, PCI group, n ¼ 89, normal coronary angiography group, n ¼ 92) underwent coronary angiography according to Judkins technique through femoral or radial approach. Patients with PCI received 100 to 300 mg of aspirin and oral loading dose of 300 mg clopidogrel, administered 12 to 24 hours before coronary stenting. Unfractionated heparin was given at the beginning of the procedure to obtain activated clotted time levels between 250 and 300 seconds for procedures. Patients with critical stenosis (70% stenosis on any of the major coronary arteries or their branches) underwent PCI in the same session. Coronary stenting procedure was performed using low osmolar, nonionic contrast agents (iopromide) with standard percutaneous techniques by experienced operators. www.ajconline.org

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Table 1 Baseline clinical, angiographic and procedural characteristics of study patients Variable

Age, mean  SD Women Body Mass Index (kg/m2) Waist circumference, (cm) Hypertension* Diabetes Mellitus Smoker Hyperlipidemia† Prior myocardial infarction Prior coronary bypass Creatinine (mg/dl) Total cholesterol (mg/dl) Low-density lipoprotein (mg/dl) High-density lipoprotein (mg/dl) Triglyceride (mg/dl) Baseline medication Statin Beta-blocker Nitrate Angiotensin-converting enzyme inhibitors/ Angiotensin receptor blockers Silent cerebral infarct (þ), (Neuron specific enolase 0.12)

Normal Elective P value coronary percutaneous angiography coronary (n¼92) intervention (n¼89) 6111 58(63%) 275

6210 21(24%) 275

0.5 <0.001 0.6

1178 61(66%) 25(27%) 6(7%) 37(40%) 0 (0%) 0 (0%) 0.80.2 18642 11037 4615 16333

10213 68(76%) 36(40%) 34(38%) 56(63%) 29(33%) 12 (14%) 1.11.0 18237 11339 4516 14263

<0.001 0.1 0.06 <0.001 0.002 <0.001 <0.001 0.02 0.5 0.6 0.6 0.6

51(55%) 40(44%) 14(15%) 50(53%)

67(75%) 53(60%) 54(61%) 66(75%)

0.005 0.02 <0.001 0.003

10(11%)

37(42%)

<0.001

* Blood pressure >140/90 mm Hg at 2 occasions or antihypertension treatment. † Fasting low-density lipoprotein (LDL) level >160 mg/dL or patients on antihyperlidemia treatment.

The inflation and stent protocol were left to the discretion of the operator. Measurements of NSEs were obtained at baseline and 12 hours after the intervention by h-NSE kits (Diametra, Foligno, Italy) with direct immunoenzymatic colorimetric method on immunologic automated analyzer. Intra-assay and interassay coefficient variabilities were 4.4% and 11.2%. Laboratory upper limits of normal were 0.12 mg/L for NSE according to manufacturers’ instruction. SCI was defined as an NSE level of >0.12 mg/L after the intervention. All patients were followed up for the occurrence of inhospital clinical events comprising stroke, death, and acute myocardial infarction (MI). For each patient, risk factors including hypertension, diabetes mellitus, hypercholesterolemia, smoking status, and history of ischemic stroke were obtained. All analyses were performed using an SPSS software package (version 16.0 for Windows, SPSS Inc., Chicago, Illinois). Data are expressed as numbers and percentages for discrete variables and as means  SD for continuous variables. The chi-square analysis was used to assess the significance of differences between categorical variables. Continuous variables were compared by Student’s t test or ManneWhitney U test. In univariate analysis, age, gender, body mass index, waist circumference, present cigarette

Figure 1. The incidence and magnitude of post-procedural NSE elevation according to study groups.

smoking, presentation of hypertension, diabetes, history of MI, history of Coronary artery bypass grafting surgery, the plasma levels of total cholesterol, low- and high-density lipoprotein and triglyceride, use of statins, beta blockers, calcium channel blockers, nitrates, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were assessed. A multivariable logistic regression analysis was performed to assess the independent predictors of NSE elevation after the procedure. Results with a p value <0.05 were considered significant. Results Baseline clinical, angiographic, and procedural characteristics of study patients are seen in Table 1. Stenting procedure was successful in all the cases with a residual diameter stenosis of <20% and thrombolysis in MI flow grade 3 after the intervention. Forty-seven of 181 study patients (26%) had SCI after the procedure. SCI was more prevalent in patients with PCI than that of those with normal coronary angiograms (42% vs 11%, p <0.001; Figure 1). When patients were divided into 2 groups according to SCI occurrence, those with SCI were more likely to have history of smoking and previous MI and less waist circumference (Table 2). Age, incidence of hypertension, hyperlipidemia, diabetes mellitus, smoking status, and history of MI and coronary bypass were statistically re-evaluated using multivariate logistic regression analysis. Multivariate analysis demonstrated history of smoking (odds ratio [OR] 9.9; 95% CI 3.7 to 26.9; p <0.001) and previous MI (OR 4.4; 95% CI 1.7 to 11.4; p ¼ 0.01) as independent predictors of SCI (Table 3). No stroke, transient ischemic attack, death, ST-elevation MI, or urgent coronary bypass was observed during hospitalization. Discussion In this cohort of 181 patients who underwent elective coronary angiography (CAG) and/or PCI, prevalence of SCI was 26% (11% in normal CAG and 42% in patients with PCI). The smoking status and previous MI were the independent predictors for the development of SCI.

Coronary Artery Disease/Silent Cerebral Infarct and Coronary Procedures Table 2 Clinical and angiographic characteristics of silent cerebral ischemia (þ) and () patients Variable

Silent cerebral infarct (þ) (n¼47)

Silent cerebral infarct (-) (n¼134)

P value

Age, mean  SD (years) Women Body Mass Index (kg/m2) Waist circumference, cm(MeanSD) Hypertension Diabetes Mellitus Smoker Hyperlipidemia Prior myocardial infarction Prior coronary bypass Coronary artery stented: Left anterior descending Left circumflex Right Saphenous graft Procedural characteristics: Multivessel disease Stent number (MeanSD) Drug eluting stent (MeanSD) Bare metal stent (MeanSD) Stent length (MeanSD) Stent size (MeanSD) Inflation pressure (MeanSD) Stenosis (MeanSD) Left ventricle ejection fraction (%)

5910 14(30%) 285 10312 36 (77%) 12 (26%) 26(55%) 29(62%) 19 (40%) 5 (11%)

6211 65(49%) 285 10914 93 (69%) 49 (37%) 14(10%) 64(48%) 10(8%) 7 (5%)

0.2 0.3 0.6 0.02 0.3 0.2 <0.001 0.1 <0.001 0.3

21 15 16 1

25 25 19 2

(57%) (41%) (43%) (9%)

20(54%) 1.91.2 0.70.9 1.11.4 3223 2.90.4 153 8516 564

(48%) (48%) (37%) (20%)

0.4 0.5 0.5 0.6

32(62%) 1.70.9 0.70.8 11.1 2616 30.4 142 8313 585

0.3 0.4 0.7 0.5 0.1 0.4 0.2 0.4 0.7

Table 3 Independent predictors of SCI in logistic regression analysis OR (95%, CI) Age Diabetes mellitus Hypertension Hyperlipidemia Smoking status Prior myocardial infarction Prior coronary bypass

2 0.5 1.21 1.15 9.95 4.43 1

(1.4-6.7) (0.19-111) (0.44-3.29) (0.48-2.77) (3.68-26.92) (1.73-11.39) (0.29-3.45)

P Value 0.2 0.1 0.7 0.8 <0.001 0.001 0.9

CI ¼ confidence interval; OR ¼ odds ratio.

NSE elevations after coronary artery bypass surgery, pulmonary vein isolation, patent foramen ovale closure, transcatheter aortic valve implantation, and other cardiac interventions have been reported previously.10 NSE elevation after PCI has also been studied. In 2 acute coronary syndrome trials, NSE elevation was detected in 32% to 35% of patients after emergency PCI.11,12 Thrombogenic environment and cerebral embolization from the ostial coronary lesions may contribute to the genesis of SCI in the setting of ACS. In the present trial, we excluded patients with ACS. Thus, our results should be interpreted in the context of elective PCI. Recently, Busing et al13 demonstrated that elective PCI and diagnostic angiography elicited an increased risk for the development of SCI. In this study, they found that elective PCI have a risk for the development

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of SCI on magnetic resonance imaging (MRI) compared with diagnostic angiography (23% vs 11%, p ¼ 0.37). Our study confirms their findings in a larger population. Besides, our study is first to demonstrate that NSE elevation can be seen in patients with normal coronary angiograms who are supposed to have low atherosclerotic burden compared with those with significant lesions. Several studies indicate a strong, independent association between atherosclerotic disease of aortic arch and ischemic stroke.14 It has been previously shown that the existence of atheromatous material in the aorta increases the risk of stroke during cardiac catheterization.15 During invasive cardiac procedures, dislodgement of this material from the aorta, especially thick plaque, may cause cerebral embolization, resulting in ischemic neurologic complications.16 Induced platelet activation because of vascular injury from stent placement may also contribute to the genesis of silent or clinically important cerebrovascular events in patients who underwent elective PCI. Because patients with normal CAG are expected to have less atherosclerotic process on aorta, the mechanism of thromboembolism may be different in this patient population. One possible mechanism for the NSE elevation may be the formation and embolization of thrombus secondary to the catheter manipulation and endothelial damage.14,15 Also thrombus formation at the catheter tip, air embolism, and contrast agent11,17,18 may constitute other possible causes of SCIs. The present study has several potential limitations. One limitation is that cranial MRI which has been the gold standard method to detect cerebrovascular injury19 was not performed. However, both NSE levels and MRI have similar results for detecting infarct size, and significant correlation has previously been reported between NSE and stroke severity.19e21 Another limitation is that this study was a single-center trial with few patients. Therefore, the results of the study should be interpreted with caution. Our study demonstrates that SCI is common in patients who underwent elective PCI. It can occur even in patients with normal coronary arteries. Given the increased number of diagnostic and interventional coronary procedures, substantial number of patients are at increased risk for SCI development. This may lead to decreased cerebral functions in long term especially in patients with recurrent interventions. Strategies to prevent SCI may be of importance. High incidence of SCIs after the interventional procedures warrant further studies to assess their prognostic implications and to develop preventive and therapeutic strategies. Disclosures The authors have no conflicts of interest to disclose. 1. Kaiser E, Kuzmits R, Pregant P, Burghuber O, Worofka W. Clinical biochemistry of neuron-specific enolase. Clin Chim Acta 1989;183: 13e31. 2. Price TR, Manolio TA, Kronnal RA, Kittner SJ, Yue NC, Robbins J, Anton-Culver H, O’Leary DH. Silent brain infarction on magnetic resonance imaging and neurological abnormalities in communitydwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Stroke 1997;28:1158e1164. 3. Avdibegovic E, Becirovic E, Salimbasic Z, Hasanovic M, Sinanovic O. Cerebral cortical atrophy and silent brain infarcts in psychiatric patients. Psychiatr Danub 2007;19:49e55.

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