Assessment of silent brain injury in patients undergoing elective percutaneous coronary intervention due to chronic total occlusion

Abstract

Objective: Silent brain infarcts (SBI) are thromboembolic complications associated with cardiac surgery, diagnostic angiography, and percutaneous interventions. Serum neuron-specific enolase (NSE) is the proven biomarker for measuring neuronal damage. This study aimed to evaluate the incidence of SBI, defined as elevated NSE after coronary chronic total occlusion (CTO) intervention and elective coronary stenting. Design: The study population consisted of two patient groups: the CTO group included consecutive patients with coronary CTO intervention, and the control group consisted of patients who underwent elective coronary intervention. NSE blood levels were measured before and 12–18 h after the procedure. NSE blood levels of >20 ng/mL were considered SBI. Results: A total of 108 patients were included in the study. Of these, 55 (50.9%) had SBI after the procedure. The SBI rate was 59.7% in the CTO group and 39.1% in the control group. Patients with SBI were more likely to have diabetes mellitus, hyperlipidemia, higher HbA1c, higher total stent length, and longer procedural time. Multivariate logistic regression analysis showed that CTO procedure (odds ratio [OR]: 3.129; 95% confidence interval [CI]: 1.246–7.858; p < 0.015) and diabetes mellitus (OR: 2.93; 95% CI: 1.185–7.291; p < 0.020) are independent predictors of SBI. Conclusion: Our data suggest that SBI occurs more frequently after CTO intervention than after non-CTO intervention. Intervention complexity and patient clinical characteristics may explain the increased incidence.

Keywords:

• Neuron-specific enolase
• chronic total occlusion
• silent brain infarct
• coronary intervention
• cerebral infarct
• stroke

Introduction

The most complex percutaneous coronary intervention (PCI) cases are chronic total occlusions (CTO). Due to the histological nature of the occluded vessel, the probability of success is low, while the risk of complications is high [1]. This case group has been evaluated previously for many complications, and scoring systems have been established [2,3]. Silent brain infarct (SBI) is defined as evidence of cerebral infarction in the absence of clinical stroke or transient ischemic attack (TIA) [4]. Although SBI is more prevalent than clinically-apparent stroke or TIA, major ischemic cerebrovascular accidents are well-studied due to their clinical significance [5]. SBI may be associated with neurologic deficits, cognitive decline, psychiatric disorders (i.e. depression, dementia), clinically-apparent stroke, and increased mortality [6–12]. The gold standard method for detecting brain injury is the cranial magnetic resonance imaging (MRI) modality [13]. However, biomarkers such as neuron-specific enolase (NSE), S100-B, glial fibrillary acidic protein (GFAP), and the tubulin-associated unit can also be used to measure neuronal damage [14]. NSE may be a valid biomarker for quantifying the volume of neuronal damage [15,16]. NSE is a cytoplasmic enzyme found in neurons that elevates at around 2–4 h after acute neuronal damage, reaches a peak level at 12–18 h, and remains positive in the blood for approximately 3 days [17]. Moreover, NSE blood level is directly associated with the brain infarct volume and is a predictor of ischemic stroke [18,19]. In this study, we aimed to evaluate the incidence of SBI, defined as elevated NSE after coronary CTO intervention and elective coronary stenting, and procedural factors affecting SBI.

Materials and methods

The study population consisted of two patient groups enrolled between January and October 2019. The CTO group included 62 consecutive patients with coronary CTO intervention; the control group consisted of 46 consecutive patients who underwent elective coronary intervention. Patients who underwent PCI to a single coronary artery were preferred for both groups. CTO was defined as antegrade thrombolysis in myocardial infarction (TIMI) grade 0 flow in the distal end of the coronary artery for at least 3 months.

Exclusion criteria were baseline NSE elevation; acute coronary syndromes (ACS) or cardiac surgery within the past 4 weeks; patients with advanced aortic and mitral valve dysfunction and prosthetic valve implantation; patients currently in atrial fibrillation rhythm or with a history of atrial fibrillation in the past; patients with a cerebrovascular accident, intracranial hemorrhage, or head trauma; the presence of central nervous system tumor, degenerative central nervous system disorders, and neuroendocrine tumors. Additional exclusion criteria include hemodynamic deterioration between two NSE measurements, malignant arrhythmia, myocardial infarction, palpable clinical stroke, TIA, acute stent thrombosis, and left main coronary artery (LMCA) PCI.

Our study complies with the principles of the Declaration of Helsinki. All patients gave written informed consent, and the Ondokuz Mayıs University clinical research ethics committee approved the study protocol. The study protocol was also registered to ClinicalTrials.gov (Protocol Registration and Results System) with the number NCT04734587.

OA physical examination, ECG, and echocardiography were performed on each patient before PCI. Only neurologically intact patients were included. All patients were monitored for the occurrence of in-hospital clinical events and complications, including stroke, transient ischemic attack, arrhythmia, pseudoaneurysm, hematoma, hemorrhage, acute renal failure, coronary dissection, and acute myocardial infarction. We obtained risk factors for each patient, including hypertension, diabetes mellitus, hypercholesterolemia, smoking status, and history of PCI or CABG. The number of catheters, microcatheter, stents, wire, and balloons, as well as contrast amount and procedure time, were also recorded.

Patients underwent PCI according to Judkins Technique using the femoral approach. They were administered 100–300 mg of aspirin and an oral loading dose of 600 mg clopidogrel 12–24 h before PCI. Unfractionated heparin (70 mg/kg) was administered at the beginning of the procedure to obtain activated clotted time levels above 300 s. The coronary stenting procedure was performed by an experienced operator (KS) using low osmolar, nonionic contrast agents iopromide (Ultravist^® 370, Bayer).

Bilateral transfemoral 7 F extra backup catheter was the primary preference in CTO procedures; dual injection was administered to all patients. Retrograde CTO PCI was preferred for eligible patients, while antegrade CTO PCI was preferred for others. 6 F Judkins catheter, floppy wire, and transfemoral route were preferred in patients with non-CTO elective coronary intervention (control group).

Blood samples were collected from the antecubital vein for complete blood count (CBC), glucose, alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), bilirubin, creatinine, sodium, and potassium analyses 2 h before the intervention. CBC was determined using Sysmex Automated Hematology Analyzer XN-100 (Japan). Serum AST, ALT, creatinine, bilirubin, and LDH concentrations were studied using Roche Hitachi Cobas 8000 (Japan) device with Roche Diagnostics GmbH kits. All assays were conducted according to the manufacturer’s instructions.

The NSE blood samples were taken at baseline (before 2 h) and 12–18 h after the intervention. Samples were centrifuged (Shimadzu UV160A, S. No: 28006648, Japan) at 3000 × g for 10 min; the sera were then stored at −80 °C. NSE measurements were obtained using human-NSE ELISA kits (SunredBio, Shanghai, China). Intra- and inter-assay coefficient variabilities were <10% and <12%, respectively. Laboratory upper normal limits were 20 ng/mL for NSE as defined by the manufacturer’s instruction. SBI was defined as an NSE level of >20 ng/mL after the intervention.

Compliance with normal distribution was examined using the Kolmogorov–Smirnov and Shapiro–Wilk tests. The independent sample t-test was used to compare normally distributed data; the Mann–Whitney U-test was used to compare non-normal distribution data. The Chi-square test was used to compare categorical data. Data showing normal distribution were presented as mean ± standard deviation, while data not matching the normal distribution were presented as median (min.–max.). Categorical data were presented as frequency (percentage). For determining independent predictors of the high SBI in both groups, univariable logistic regression analysis was used, and those that showed significant association with high SBI were included in multivariable analysis including the presence of hypertension, DM, hyperlipidemia, smoking, ejection fraction, total contrast amount, procedure time and type of procedure (CTO or non-CTO). Results with a p-value <0.05 were considered significant. All analyses were performed using an SPSS software package (version 23.0 for Windows, SPSS Inc., Chicago, IL).

Results

After pre-evaluation, 120 patients met the study criteria; 12 of them were excluded for the following reasons: one had myocardial infarction from another coronary artery within 24 h, one had acute stent thrombosis, one had a stroke during the intervention, one had transient ischemic attack after PCI, one had ventricular fibrillation, two underwent unplanned LMCA stenting, one had hypotension requiring inotropic agent, and four had elevated baseline NSE. Finally, the study population comprised 108 patients (87% male) with a mean age of 62 years. When the baseline patient characteristics were evaluated, it was observed that parameters other than smoking were similar in both groups. The smoking rate (32.8% vs 19.6% p = 0.004) was higher in the CTO group than in the control group. The median J-CTO score of patients with CTO was 1 (0–3). Except for two patients, the antegrade route was used in all patients with CTO. The percutaneous coronary intervention was completed successfully in 54 patients with CTO. The procedure failed (TIMI 0 flow) in six patients using the antegrade technique and two using the retrograde technique. All patients in the non-CTO group completed stent implantation and TIMI 3 flow. The patient’s baseline NSE values were also similar in the CTO and control groups [9.9 (5–16.2) vs 10.2 (4–17.4), p = 0.506] (Table 1).

Table 1. Baseline characteristics of the study groups.

	CTO Group (n = 62)	Control Group (non-CTO) (n = 46)	Total (n = 108)	p-Value
Clinical and hemodynamic data
Age, years	61.9 ± 11.3	61.9 ± 8.7	61.9 ± 10.2	1.000
Men, n (%)	52 (83.9)	35 (76.1)	87 (80.6)	0.444
Body mass index, kg/m^2	29.2 ± 4.7	27.7 ± 2.7	28.5 ± 3.9	0.051
Diabetes mellitus, n (%)	25 (40.3)	24 (52.2)	49 (45.4)	0.221
Hypertension, n (%)	56 (90.3)	36 (78.3)	92 (85.2)	0.141
Hyperlipidemia, n (%)	54 (87.1)	36 (78.3)	90 (83.3)	0.223
Smoking, n (%)	20 (32.8)	9 (19.6)	29 (27.1)	0.004
Prior PCI, n (%)	29 (46.8)	25 (54.3)	54 (50)	0.559
Prior CABG, n (%)	3 (4.8)	2 (4.3)	5 (4.6)	0.904
Biochemical and echocardiographic data
Total cholesterol, mmol/L	4.57 ± 1.11	5.25 ± 4.88	4.88 ± 3.41	0.362
Low-density lipoprotein, mmol/L	2.66 ± 0.93	2.58 ± 1.11	2.63 ± 1	0.709
High-density lipoprotein, mmol/L	0.98 (0.51–2.04)	0.9 (0.56–2.04)	0.93 (0.51–2.04)	0.253
Triglyceride, mmol/L	1.64 (0.6–14)	1.67 (0.66–5.21)	1.65 (0.6–14.7)	0.155
Creatinine, μmol/L	79.56 (53.04–185.64)	79.56 (44.2–150.28)	79.56 (44.2–185.64)	0.720
HbA1C, %	6.8 (5.3–11)	6.9 (5.5–16.9)	6.8 (5.3–16.9)	0.324
Hemoglobin, g/L	135 (90–167)	133 (97–159)	134 (90–167)	0.274
LVEF, %	52.4 ± 9.2	56.3 ± 9.1	54.1 ± 9.3	0.056
LA, mm	35.9 ± 3.6	35.8 ± 4.9	35.9 ± 4.1	0.881
Medication
Beta-blocker, n (%)	51 (85)	34 (75.6)	85 (81)	0.223
CCB, n (%)	16 (26.7)	8 (17.8)	24 (22.9)	0.283
ACE-I/ARB, n (%)	44 (73.3)	28 (62.2)	72 (68.6)	0.225
Statin, n (%)	43 (71.7)	31 (68.9)	74 (70.5)	0.926

Continuous variables are presented as mean ± standard deviation if normally distributed, and as median (min.–max.) if otherwise. Categorical variables are presented as frequency (percentage). p < 0.05 (in bold) was considered as statistically significant.

ACE-I: angiotensin-converting enzyme (ACE) inhibitors; ARB: angiotensin II receptor blockers; CABG: coronary artery bypass graft; CCB: calcium channel blocker; LA: left atrium; LVEF: left ventricular ejection fraction; NSE: neuron-specific enolase; PCI: percutaneous coronary intervention.

Upon examining the procedural parameters, the groups were similar in pre-procedural blood pressure, preferred P2Y12 inhibitor, and the method of implanting the coronary stent. The guiding catheter size, the number of implanted stents, total stent length, total contrast amount, fluoroscopy time, and total procedural time was significantly higher in the CTO group compared to the non-CTO group (Table 2). Basal creatinine levels were the same (79 µmol/L) for both groups. In the post-procedural follow-up, none of the patients developed acute renal failure.

Table 2. Comparison of the procedure parameters and NSE value between the CTO and control (non-CTO) groups.

	CTO Group (n = 62)	Control Group (n = 46)	Total (n = 108)	p-Value
Femoral approach, n (%)	62 (100)	46 (100)	108 (46.2)	1
Systolic BP, mmHg	128 (97–163)	130 (113–150)	130 (97–163)	0.132
Diastolic BP, mmHg	78.5 (64–105)	75 (60–96)	76 (60–105)	0.054
Target vessel, n (%)				0.132
LAD	33 (53.2)	20 (43.5)	53 (49.1)
Cx	8 (12.9)	14 (30.4)	22 (20.4)
RCA	21 (33.9)	12 (26.1)	33 (30.6)
J-CTO score	1 (0–3)
P2Y12 inhibitors, n (%)				0.478
Clopidogrel	55 (88.7)	37 (80.4)	92 (85.2)
Ticagrelor	5 (8.1)	6 (13)	11 (10.2)
Prasugrel	2 (3.2)	3 (6.5)	5 (4.6)
ASA, n (%)	62 (100)	46 (100)	108 (100)	1
UFH, n (%)	62 (100)	46 (100)	108 (100)	1
Catheter size, median (min.–max.)	7 (6–7)	6 (5–7)	7 (5–7)	<0.001
Number of stents, median (min.–max.)	2 (0–4)	1 (1–2)	1 (0–4)	0.011
Total stent length, mm	54.6 ± 22.2	32.5 ± 13.7	45.3 ± 21.9	<0.001
Final TIMI flow, median (min.–max.)	3 (0–3)	3 (2–3)	3 (0–3)	0.014
Total contrast, mL, median (min.–max.)	200 (100–400)	80 (40–180)	160 (40–400)	<0.001
Fluoroscopy time, min, median (min.–max.)	25 (12–88)	8.5 (6–11)	25 (6–88)	0.017
Procedure time, min, median (min.–max.)	55 (22–230)	32 (13–78)	45 (13–230)	<0.001
Total number of used materials, n	11.7 ± 3.5	7 ± 1.7	9.7 ± 3.7	<0.001
Baseline NSE, ng/mL (min.–max.)	9.9 (5–16.2)	10.2 (4–17.4)	9.9 (4–17.4)	0.632
Final NSE level, ng/mL (min.–max.)	29.6 (6–78.7)	13.2 (4.6–88.2)	21.8 (4.6–88.2)	0.079
NSE differences before–after PCI	19.7 (3.5–69.9)	1.4 (3.8–79.9)	9.6 (3.5–79.9)	0.113
SBI (NSE > 20ng/mL), n (%)	37 (59.7)	17 (37.0)	54 (50)	0.020

Continuous variables are presented as mean ± standard deviation if normally distributed, and as median (min.–max.) if otherwise. Categorical variables are presented as frequency (percentage). p < 0.05 (in bold) was considered statistically significant.

ASA: acetylsalicylic acid; BP: blood pressure; CTO: chronic total occlusion; NSE: neuron-specific enolase; TIMI: thrombolysis in myocardial infarction; UFH: unfractionated heparin.

In the present study, we found that 54 (50%) of the 108 patients had SBI (>20 ng/mL). NSE positivity was more prevalent in the CTO group than the non-CTO group (37 [59.7%] vs 17 [37%], p = 0.020). The final NSE was 29.6 (6–78.7) ng/mL in the CTO group and 13.2 (4.6–88.2) ng/mL in the control group (p = 0.079). NSE differences (delta values) before and after intervention for the CTO and non-CTO groups were 19.7 (3.5–69.9) ng/mL and 1.4 (3.8–79.9) ng/mL, respectively. When study participants were grouped by SBI status, those with diabetes mellitus, hyperlipidemia, higher HbA1c, longer total stent length, and procedural time were more likely to have SBI (Table 3). These parameters, which were elevated in the group with SBI, were re-evaluated using multivariate logistic regression analysis. Multivariate logistic regression analysis demonstrated CTO procedure (odds ratio [OR]: 3.129; 95% confidence interval [CI]: 1.246–7.858; p < 0.015) and diabetes mellitus (OR: 2.93; 95% CI: 1.185–7.291; p < 0.020) as independent predictors for SBI (Table 4).

Table 3. Study groups according to SBI (NSE positivity).

	SBI positive (n = 54)	SBI negative (n = 54)	p-Value
Age, years	62.1 ± 9.9	61.8 ± 10.8	0.90
J-CTO score	1.34 ± 1.00	1.08 ± 0.776	0.29
Sex (men), n (%)	44 (81.5)	42 (79.2)	0.48
CTO procedure, n (%)	37 (68.5)	25 (46.3)	0.01
Hyperlipidemia, n (%)	49 (90.7)	41 (75.9)	0.03
Diabetes mellitus, n (%)	30 (55.6)	19 (35.2)	0.02
Smoking, n (%)	23 (42.6)	19 (34.8)	0.26
Prior CABG, n (%)	2 (3.7)	3 (5.6)	0.50
Prior PCI, n (%)	30 (55.6)	23 (42.6)	0.12
HbA1c (%)	7.94 ± 2.46	6.70 ± 1.16	0.01
LVEF (%)	53.2 ± 8.9	55.1 ± 9.6	0.37
Number of stents, n	2 (0–4)	1 (0–3)	0.08
Total stent length, mm	50.16 ± 25.58	40.92 ± 17.17	0.04
Procedural time, min	54.25 ± 35.86	43.60 ± 18.42	0.06

Continuous variables are presented as mean ± standard deviation if normally distributed, and as median (min.–max.) if otherwise. Categorical variables are presented as frequency (percentage). p < 0.05 (in bold) was considered statistically significant.

HbA1c: hemoglobin A1c; CABG: coronary artery bypass graft; CTO: chronic total occlusion; LVEF: left ventricular ejection fraction; PCI: percutaneous coronary intervention; SBI: silent brain infarct.

Table 4. Independent predictors of SBI in binary logistic regression analysis.

	Univariate logistic regression analysis			Multivariate logistic regression analysis
	OR	95% CI	p-Value	OR	95% CI	p-Value
CTO procedure	2.63	1.19–5.78	0.016	3.12	1.24–7.85	0.015
Diabetes mellitus	2.43	1.11–5.31	0.026	2.93	1.18–7.29	0.020
Hypertension	1.86	0.62–5.54	0.265
Smoking	1.40	0.63–3.07	0.400
LVEF, %	0.97	0.92–1.02	0.244
Procedure time, min	1.01	0.99–1.03	0.070
Total contrast, mL	1.00	0.99–1.00	0.315
Prior PCI	1.63	0.76–3.49	0.210
Prior CABG	0.64	0.10–3.99	0.634
Hyperlipidemia	3.18	1.04–9.69	0.041

CABG: coronary artery bypass graft; CI: confidence interval; LVEF: left ventricular ejection fraction; OR: odds ratio; NSE: neuron-specific enolase; PCI: percutaneous coronary intervention. p < 0.05 (in bold) was considered statistically significant.

Discussion

CTO procedure was associated with a significantly higher risk of SBI than non-CTO coronary stenting. CTO procedure and the presence of diabetes mellitus functioned as independent predictors for developing SBI.

SBI has been investigated in several studies after cardiac procedures (e.g. coronary artery bypass surgery, pulmonary vein isolation, patent foramen ovale closure, and transcatheter aortic valve implantation) [20–23]. In a recent meta-analysis by Cho et al. [24], 833 patients who underwent diagnostic coronary procedures were evaluated with a complete neurological examination and diffusion MRI before and after the procedure. Although the clinical symptomatic stroke incidence was 0.6%, radiographic brain infarction was 13 times higher (8%) [24]. In their NSE study, Göksülük et al. [25] found the SBI rate to be 11% in elective coronary angiography and 42% in PCI procedures. Similarly, in our study, SBI was found in 37% of the control group who underwent non-CTO PCI.

SBI was also evaluated according to the clinical presentation and intervention route of the patient who underwent PCI [26–28]. Increased thrombus formation and embolization from coronary ostium may contribute to the development of SBI in patients with ACS [27]. Stroke was more frequent during PCI performed by operators with less experience with the radial approach and, the risk of cardiovascular complications and stroke tended to be higher with the left radial approach, particularly in ACS patients [29]. In another study in which NSE elevation was evaluated, the risk of SBI was found more frequently with the transradial approach [30]. In addition, access site crossover also increases the risk of stroke [31,32]. Therefore, in this study, patients with ACS were excluded, and the transfemoral approach was thus preferred.

Many studies have demonstrated that a relationship exists between aortic atherosclerosis and stroke [33]. We did not evaluate aortic atherosclerosis directly; however, we observed that hyperlipidemia is an indirect marker higher in the SBI + patient group. Using wire, microcatheter, and balloon manipulation to penetrate the calcified CTO segment increases the rate of coronary perforation [34]. Also forces the catheter into more contact with the aorta. In CTO procedures, two catheters should be used simultaneously in the aorta. SBI may occur due to the embolization of atheroma or thrombus, developing on the damaged endothelium by manipulating plaques on the aorta and proximal carotid surface of the wire and catheters [35]. Moreover, as seen in our study, more material reaches the coronary by passing through these catheters in CTO procedures compared to the control group. In addition, thrombus formation may occur on the wire or catheter [36,37].

Aykan et al. [38] showed that more complex coronary artery disease (high syntax score) was associated with increased NSE levels in patients with ACS (acute coronary syndrome) who underwent PCI. CTOs are complex lesions. Compared to the control group, our study confirms that the risk of increased SBI is also present in complex percutaneous coronary interventions without ACS. Deveci et al. [39] demonstrated an increased SBI rate with an extended procedural time. Using contrast agents can cause neuronal damage through vasospasm caused by the cerebral arteries or by passing through the blood–brain barrier [40]. The amount of contrast used and the procedural duration is longer in CTO interventions than in non-CTO interventions. According to our findings, both parameters are associated with an increased SBI rate.

In this study, we found that the risk of SBI due to percutaneous coronary intervention is high in patients with diabetes. Subgroup analysis demonstrated that HbA1c level was also associated with increased SBI. Diabetes increases atherosclerosis and atherothrombosis by causing increased systemic inflammation, oxidative stress, endothelial dysfunction, platelet dysfunction, impaired coagulation, and decreased fibrinolysis [41,42]. Poor glycemic control increases the atherosclerotic and thrombogenic effects of diabetes [43]. In their study, Ravipati et al. observed that the prevalence of coronary atherosclerosis increases with higher HbA1c levels [44]. The results of our study are consistent with those of previous studies, showing the relationship between diabetes and SBI. We showed that HbA1c might be a candidate marker for predicting the risk of SBI in patients with diabetes.

This study has some limitations. First, the diagnosis of SBI was not confirmed by MRI. Cranial MRI is the gold standard for detecting cerebral ischemia [45]. However, cranial MRI may not detect lesions smaller than 2 × 1.8 mm² [46,47]. Biochemical markers, such as NSE and S100-B, may be more sensitive in these clinical situations [15,48]. However, NSE is suggested to be a valid biomarker that allows for quantification of the degree of neuronal infarct [16]. Furthermore, NSE levels had a reasonable correlation with MRI [45,49]. Another limitation is that NSE may be elevated in liver injury, kidney injury, hypoperfusion, trauma, bone fractures, or undiagnosed cancer [15]. We excluded incidental NSE elevation from causes other than undiagnosed neuronal damage by performing baseline measurements in the current study.

Conclusions

Increased incidence of SBI due to PCI in CTO interventions appears to be related to procedural parameters. Although SBIs are clinically ‘silent,’ they are associated with long-term morbidity. Therefore, care should be taken during CTO and similar complicated percutaneous cardiac procedures, particularly in patients with diabetes, because of the risk of SBI.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was financially supported by Ondokuz Mayıs University with the project number PYO.TIP.1904.19.004.