Excimer laser coronary angioplasty versus manual aspiration thrombectomy in patients with ST-segment elevation myocardial infarction: analyzed by nuclear scintigraphy

Clinical outcomes concerning the efficacy of excimer laser coronary angioplasty (ELCA) in real-world cases of acute myocardial infarction (MI) are limited. We evaluated and compared the impact of ELCA with manual aspiration thrombectomy on myocardial salvage and left ventricular (LV) systolic/diastolic function in patients with ST-segment elevation MI (STEMI) using nuclear scintigraphy. We enrolled 143 consecutive patients with STEMI treated with ELCA (63 patients) or manual aspiration thrombectomy (80 patients) between September 2016 and December 2020 in a single-center hospital. We evaluated the peak creatine kinase (CK)/ creatine kinase-myocardial band (CK-MB) levels and performed single-photon emission computed tomography (SPECT) analyses with Quantitative Gated SPECT and Quantitative Perfusion SPECT (Auto QUANT 7.2) at 3–10 days using 123I-BMIPP and 3 months following percutaneous coronary intervention using 99mTc-tetrofosmin to evaluate myocardial salvage and LV systolic/diastolic function. No significant difference was observed in the patient and periprocedural characteristics. Peak CK-MB level was significantly different between the groups (ELCA group, 190.0 [70.5–342.0] IU/L vs. aspiration group, 256.5 [157.0–354.8] IU/L, p = 0.047). Although no significant difference was observed in myocardial salvage, significant improvement in the LV ejection fraction (14.1 [6.2–19.8]% vs. 9.5 [3.9–15.3]%, respectively, p = 0.018) and peak emptying rate (-0.54 [-1.02– (-0.27)] mL/s vs. -0.38 [-0.76– (-0.05)] mL/s, respectively, p = 0.017) were detected. ELCA could suppress the myocardial deviation enzymes and potentially improve systolic function compared to manual aspiration thrombectomy in patients with STEMI.

efficacies of ELCA, such as a reduction in the number of devices, improvement of thrombolysis in myocardial infarction (TIMI) flow grade, and myocardial salvage in patients with ACS, LV function improvement has not been demonstrated [10][11][12][13]. Therefore, we evaluated and compared the impact of ELCA on myocardial salvage and improvement of LV function with manual aspiration thrombectomy using nuclear scintigraphy in patients with ST-segment elevation MI (STEMI).

Patient recruitment
We enrolled 571 patients with STEMI who underwent primary PCI between September 2016 and December 2020 in our institute based on an ongoing, retrospective, single-centered, hospital-based registry. We excluded 39, 91, and 224 patients with in-hospital death, who underwent PCI without ELCA or manual aspiration thrombectomy, and without scintigraphic data, respectively; 74 patients who underwent both ELCA and manual aspiration thrombectomy were subsequently excluded. Finally, 63 and 80 patients who underwent ELCA (ELCA group) and manual aspiration thrombectomy (aspiration group), respectively were enrolled in the present study (Fig. 1).
STEMI was diagnosed based on the 2018 Japanese Circulation Society guideline [1]. Written informed consent was obtained from each patient or a relative before or after undergoing PCI. This study was approved by the Medical Ethics Committee of Ogaki Municipal Hospital and was conducted in accordance with the Declaration of Helsinki.

Catheter procedure
Patients with STEMI were administered 200 mg aspirin, 20 mg prasugrel, and 10 mg atorvastatin before undergoing PCI. Patients were also administered 5000 U heparin in an initial bolus and in additional doses to maintain an activated clotting time > 250 s during the procedure. After ELCA became available in September 2016 at our institute, ELCA or manual aspiration thrombectomy was performed at the discretion of the attending physician based on angiographic, intravascular ultrasound, or optical coherence tomography imaging.
A pulsed-wave xenon chloride excimer laser (X-80 Vitesse RX, Phillips Japan, Tokyo, Japan) at a wavelength of 308 nm, pulse duration of 135 ns, and output of 165 mJ/ pulse was employed; the fluence was 30-80 mJ/mm 2 at pulse repetition rates of 25-80 Hz. The laser catheters were available in sizes of 0.9, 1.4, and 1.7 mm. For the antegrade delivery of the laser catheter, we used safe laser techniques and injected saline before and during the laser procedure at a catheter advancement rate of 0.5 mm/s [14]. The retrograde laser method (frequency and repetition rate were raised to 60 mJ/mm 2 and 40 Hz at the maximum, respectively and the catheter was pulled back and saline was subsequently injected) was performed at the discretion of each physician. After ELCA ablation or manual thrombus aspiration, the patients underwent balloon dilatation, if necessary, and drug-eluting stents were deployed. Antegrade flow and microvascular circulation following PCI were assessed using the TIMI flow grading scale [15].

Data collection
After PCI, the clinical and demographic data of all the patients were retrieved from our hospital's medical records. We measured the serum creatine kinase (CK) and CK-myocardial band (CK-MB) values every 4 h until we identified the peak concentrations and verified the 12-lead electrocardiogram when entering the high care unit. We defined complete ST resolution as a return to a normal ST-segment on a 12-lead electrocardiogram following reperfusion therapy, and ST-segment elevation exacerbation as an increased ST-segment elevation at the time of high care unit entry compared to that on admission. Nearly all the patients were administered 100 mg aspirin and 3.75 mg prasugrel once daily for at least 1 month following the procedure.

Scintigraphic data
The methodology of the nuclear scintigraphic study is shown in Fig. 2. I-123 β-methyl-p-iodophenyl-pentadecanoic acid ( 123 I-BMIPP) has been used to investigate impaired fatty acid metabolism, which is expressed at-risk myocardium regions. 123 I-BMIPP scintigraphy was performed 1 week (3-10 days) after the initial PCI procedure. Considering the scanning procedure, 111 MBq of 123 I-BMIPP was injected while the patient was at rest in a fasting state for at least 3 h.
Image acquisition was demonstrated 15 min after injection. A wide field-of-view dual-head detector camera (Symbia Evo Excel, Siemens Co., Tokyo, Japan) was equipped with a low-energy, high-resolution collimator without X-ray-based attenuation correction. Each time, 32 views were collected over 180° from the right anterior to the left posterior oblique positions at 60-70 s/view using a step-and-shoot method. The energy discrimination was centered at 159 keV with a 20% window. A series of transaxial images were reconstructed using filtered back projection, after which cardiac short-axis and long-axis slices perpendicular to the cardiac axes were identified using a nuclear medicine computer system with a filtered back-projection algorithm without attenuation correction; short-axis, vertical long-axis, and horizontal long-axis slices, each 6 mm thick, were reconstructed. 99m Tc-tetrofosmin (TF) scintigraphy was performed 3 months following the PCI procedure. Considering the scanning procedure, 740 MBq of 99m Tc-TF was injected while the patient was at rest. Image acquisition was demonstrated using a 180° non-circular orbit with 32 steps and step-andshoot mode using a dual-head gamma camera (ADAC Ver-texPlus, Phillips, Amsterdam, Netherlands) equipped with a low-energy general-purpose collimator. The pixel size in a 128 × 128 matrix was 3.24 mm. A photopeak window of 99m Tc-TF was set at a 20% energy window centered at 140 keV. The division of the electrocardiographic R-R interval was 16 frames per cardiac cycle (50 s per step) in gated acquisition from the left inferior oblique 45° to the right anterior oblique 45°. Using a Butterworth filter with an order of 10 and a cut-off frequency of 0.49 cycle/cm, ungated reconstruction was demonstrated with filtered backprojection. No attenuation or scatter correction was applied. Horizontal and vertical long and short axes were created Fig. 2 The time series of patients with STEMI who underwent PCI. 123 I-BMIPP I-123 β-methyl-p-iodophenyl-pentadecanoic acid, Defect Ext perfusion defect area as percent of the mid-myocardial surface area, EDV end-diastolic volume, EF ejection fraction, ESV end-systolic volume, MFR/3 mean filling rate/3, Mot Ext motion abnormality area as percent of the mid-myocardial surface area, PCI percutaneous coronary intervention, PER peak emptying rate, PFR peak filling rate, QGS quantitative gated single-photon emission computed tomography, QPS quantitative perfusion single-photon emission computed tomography, SRS summed rest score, STEMI STsegment elevation acute myocardial infarction, Thk Ext thickening abnormality area as percent of the mid-myocardial surface area for single-photon emission computed tomography (SPECT) image reconstruction. The short-axis images were anonymously exported from the Digital Imaging and Communications in Medicine (DICOM) format to the quantitative myocardial perfusion (MP)-SPECT software. LV ejection fraction (LVEF) values were automatically calculated using the QGS software program (Auto QUANT 7.2, Cedars-Sinai Medical Center, Los Angeles, CA, USA). The indices were automatically derived from MP-SPECT by applying QPS. In addition, we used a 17-segment model with a five-point scoring system on polar map images according to the recommendations of the American Heart Association using a commercially available software (Heart Score View, Nihon Medi-Physics Co. Ltd., Tokyo, Japan) [16]. For cases in which the fully automated LV segmentation failed or generated unsatisfactory results, we adapted the manual mode to supply constraints to the LV segmentation algorithm by well-trained radiological technologists.
Furthermore, we evaluated the LVEF, number of patients with LVEF recovery, summed rest score (SRS), motion extent (Mot Ext, motion abnormality area as a percentage of the mid-myocardial surface area), thickening extent (Thk Ext, thickening abnormality area as a percentage of the mid-myocardial surface area), defect extent (Defect Ext, perfusion defect area as a percentage of the mid-myocardial surface area), peak emptying rate (PER), peak filling rate (PFR), and mean FR (MFR/3) [17]. LVEF, Mot Ext, and PER represent the systolic performance of the LV, whereas SRS, Thk Ext, and Defect Ext represent the viability of the residual myocardium. PFR and MFR/3 represent the diastolic performance of the LV. We defined EF recovering as patients with improved LVEF according to 99m Tc-TF scintigraphy at 3 months compared to that of baseline 123 I-BMIPP scintigraphy. We also defined dif as the difference between 99m Tc-TF scintigraphic and 123 I-BMIPP scintigraphic values at 3 months and baseline, respectively for each parameter. All the SPECT analyses were performed using the latest QGS/QPS version (Auto QUANT 7.2) by an expert radiological technologist who was blinded to the patients' baseline characteristics and clinical courses.

Study endpoints
The study efficacy endpoint was defined as the improvement in the systolic/diastolic function and viability of the LV according to the scintigraphic parameters. We also evaluated the peak serum CK/CK-MB concentrations, final TIMI flow, complete ST-segment resolution, and ST-segment elevation exacerbation. In-hospital major adverse cardiocerebral events (MACCEs), including cardiovascular death, MI (which included stent thrombosis), and stroke, were also investigated. Death was considered of cardiac origin unless an obvious non-cardiac cause was identified. Spontaneous MI and stent thrombosis were defined according to the Academic Research Consortium definitions [18]. Procedural complications included perforation, oozing rupture, slow flow/no reflow, and distal embolism.

Statistical analysis
Continuous variables are expressed as means ± standard deviations, and categorical variables are expressed as numbers and relative frequencies. Continuous variables were compared using the Student's t-test and Wilcoxon rank-sum test, and categorical variables were compared using the chisquare test or Fisher's exact test. Statistical significance was set at a p-value of < 0.05. All the statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [19].

Results
Patients' characteristics are presented in Table 1. They were comparable between the two groups. Nearly all the patients with STEMI in both the groups were treated with drug-eluting stents (ELCA group, 92.1% vs. aspiration group 90.0%). There was no significant difference in the medication at discharge. The 0.9-mm laser catheter was used for ELCA in nearly half of the patients. The periprocedural results and complications of the ELCA and aspiration groups are compared in Table 2. There was a significant difference in the peak CK-MB levels between the two groups (190.0 In the aspiration group, two patients had MACCEs, and both were non-fatal MIs attributed to subacute thrombosis the following day. In contrast, no in-hospital MACCEs were observed in the ELCA group. A representative case from the ELCA group is shown in Fig. 3. A 56-year-old man presented to our hospital with intermittent chest pain beginning 3 days prior. STEMI was diagnosed using a 12-lead electrocardiogram, and the patient underwent coronary angiogram/PCI. After considering the angiographic findings, we treated the patient with ELCA at the physician's discretion and deployed a drug-eluting stent. There were no procedural complications, the final TIMI grade was 3, and the peak CK/ CK-MB concentrations were 2566/230 IU/L. We conducted 123 I-BMIPP scintigraphy on day 6 of the illness (Fig. 3A), and the patient was discharged on day 13. At 3 months, we conducted an outpatient 99m Tc-TF scintigraphy (Fig. 3B) and reviewed the data concerning MACCEs. In this patient, LVEF increased from 40.0-56.6%.
Scintigraphic findings for the ELCA and aspiration groups are compared in Table 3. Significant differences in was observed, indicating recovery of LV systolic function (Fig. 4). No significant differences were observed in other parameters, which indicated salvage of the myocardium or recovery of LV diastolic function.

Discussion
In recent decades, several randomized controlled trials using manual aspiration thrombectomy or distal protection devices have failed to verify the clinical superiority of these devices in patients with ACS [5,[20][21][22][23]. Moreover, endpoints using cardiac magnetic resonance imaging or nuclear scintigraphy did not demonstrate any advantage of these devices in terms of MI size and improvement of LVEF [24]. Hence, no apparent optimal device to reduce the extent of myocardial injury and improve long-term outcomes in patients with ACS exists. Based on this study using nuclear scintigraphic data, we suggest that ELCA could suppress myocardial enzyme Fig. 3 a, b A representative patient with STEMI who underwent PCI, 123 I-BMIPP scintigraphy at baseline, and 99m Tc-TF scintigraphy at 3 months. 99m Tc-TF technetium-99m-tetrofosmin, 123 I-BMIPP I-123 β-methyl-p-iodophenyl-pentadecanoic acid, EDV end-diastolic volume, ESV end-systolic volume, MFR/3 mean filling rate/3, PCI per-cutaneous coronary intervention, PER peak emptying rate, PFR peak filling rate, STEMI ST-segment elevation acute myocardial infarction, QGS quantitative gated single-photon emission computed tomography elevations and improve LVEF in patients with STEMI compared to manual aspiration thrombectomy. Greater myocardial enzyme elevations are related to larger infarction size and impaired LVEF [25], demonstrating that peak myocardial enzyme concentrations serve as an index of cardiac prognosis. Moreover, ELCA could lead to a better prognosis owing to improvement in the LVEF and PER, thereby reducing the risk of heart failure and arrhythmogenic sudden death associated with LV systolic dysfunction. A previous study revealed that the main reason for greater myocardial salvage and improved LVEF could be related to the "stunned platelet" phenomenon, which is associated with antithrombogenicity driven by decreased platelet aggregation and reduction in platelet force development capability [26]. Although manual aspiration thrombectomy contributes to the physical elimination of thrombi, ELCA could play an important role in reducing the thrombotic burden by breaking molecular bonds (photochemical), rupturing plaque cells through heat generated at the catheter tip (photothermal), and disrupting intravascular material as vapor bubbles rapidly expand and implode (photomechanical), reducing MI in patients with STEMI [13,27,28]. Therefore, the proportion Table 3 Scintigraphic findings between ELCA group and Aspiration group.
Defect Ext perfusion defect area as percent of the mid-myocardial surface area, dif difference (at 3 months-at baseline), EDV end-diastolic volume, EF ejection fraction, ESV end-systolic volume, MFR/3 mean filling rate/3, Mot Ext motion abnormality area as percent of the mid-myocardial surface area, SRS summed rest score, PER peak emptying rate, PFR peak filling rate, Thk Ext thickening abnormality area as percent of the mid-myocardial surface area; dark red color means the parameter of systolic function of left ventricle, orange color means the parameter of the viability of left ventricle, and blue color means the parameter of diastolic function of left ventricle of stunned myocardium that recovered during the 3 months following PCI was greater in the ELCA group than in the aspiration group. In our study, although a correlation between myocardium salvage and improvement of LVEF was assumed, we only demonstrated a significant difference in the improvement of LVEF in the ELCA group. A previous study evaluating 1235 patients with MI using cardiac magnetic resonance also reported that the patients with the left anterior descending artery (LAD) as an infarct-related artery demonstrated the worst outcomes according to the area at risk, infarct size, LVEF impairment, and LV global longitudinal/ circumferential/radial strain impairment. On the other hand, the myocardial salvage index was not the worst in these patients [29]. However, the previous study did not mention the precise structured mechanism for the discrepancy. In our study, we performed PCI for LAD as the culprit lesion more frequently in the ELCA group as compared to that in the aspiration group (52.4% vs. 30.0%). This could be a possible reason for the diremption between myocardial salvage and LVEF improvement. No significant improvement in the LV diastolic function was observed in our study. LV diastolic function might be more susceptible to impairment owing to the phenomenon of reverse ischaemic cascade or postischaemic diastolic stunning [30,31].
ELCA also demonstrated a low incidence of periprocedural complications, with no in-hospital MACCEs. Although laser atherectomy has been used as an adjunct to PCI since the early 1980s, early studies have documented high complication rates and restenoses. Based on successful ELCA cases and those with complications, selection of the appropriate catheter size, fluence, and pulse repetition rate to obtain the lumen area and debulk thrombi or plaques in the culprit vessel is crucial [32]. Moreover, many studies predate the introduction of a smaller 0.9-mm catheter, which is deliverable via a 6-Fr guide catheter, permitting performing ELCA via the radial approach [33]. Hence, ELCA could be introduced more safely than manual aspiration thrombectomy in patients with STEMI.
There are three important findings in this study: (1) ELCA could suppress myocardial enzyme elevations compared to manual aspiration thrombectomy in primary PCI for patients with STEMI, (2) our nuclear scintigraphic data suggested that ELCA might potentially improve myocardial contractility compared to manual aspiration thrombectomy, and (3) no in-hospital MACCEs were observed in the ELCA group.

Limitations
This study had certain limitations. First, the study was a single-centered retrospective analysis of patients with STEMI who underwent PCI, and ELCA was used at the physician's discretion. Second, some patients could not undergo scintigraphy for various reasons, even though we performed PCI using either ELCA or manual aspiration thrombectomy. In addition, patients who died during hospitalization or had poorer physical status were not investigated in the present study owing to the lack of scintigraphic data. Hence, our findings could not justify the conclusions concerning the superiority of ELCA for all the patients with STEMI. Further dedicated randomized controlled trials and assessments of each parameter are necessary to clarify the impact of ELCA on myocardial salvage in patients with ACS. Third, although we found that ELCA could improve LVEF and peak CK-MB concentrations compared with manual aspiration thrombectomy, we did not demonstrate a significant difference in salvaging myocardium via scintigraphic data. Moreover, a previous study demonstrated only the improvement of myocardium salvage [10] but not improvement of LVEF. It might be necessary to analyze more patients with STEMI treated with ELCA to demonstrate significant differences in both parameters to support our findings. Fourth, similar to the previous study indicating the irrelevance between myocardium salvage and improvement of LVEF in MI, we were unable to explain the discrepancy. Further dedicated research to determine the precise mechanism for the discrepancy is warranted.

Conclusion
Based on nuclear scintigraphic findings, ELCA could suppress the myocardial enzymes and might potentially improve systolic function compared to manual aspiration thrombectomy in patients with STEMI. ELCA also demonstrated fewer procedural complications and adverse events; hence, ELCA is a feasible option for primary PCI in patients with STEMI.
Author contributions All the authors contributed to the study conception, design, material preparation, data collection and analysis. The first draft of the manuscript was written by KS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability
The deidentified participant data will be shared on a request basis. Kindly directly contact the corresponding author to request data sharing. All the analyzable datasets related to the study, study protocol, and statistical analysis plan will be made available. The data will become available immediately following publication, ending a year after the publication. For any purpose, the data will be shared as Excel files via E-mail.

Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Ethical approval This study was conducted in accordance with the Declaration of Helsinki. Approval was granted by the Medical Ethics Committee of Ogaki Municipal Hospital (Reference number: 20210916-9).
Consent to participate Written informed consent was obtained from each patient or a relative before or after undergoing PCI.

Consent to publish
The authors affirm that human research participants provided informed consent for publication of the images in Figure