Impact of recanalization of chronic total occlusion on left ventricular electrical remodeling

Abstract Background Successful percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is associated with reduction of cardiac mortality, as well as reducing fatal ventricular arrhythmias. The aim of this study was to evaluate the effect of recanalization of CTO on endocardial left ventricular voltages by paired electrophysiological studies. Methods Sixteen consecutive patients who underwent PCI for de novo CTO lesions were included. High‐density mapping was performed during sinus rhythm before and 8 months after PCI. According to the amplitude of bipolar electrograms, the left ventricular endocardium was classified into a preserved normal voltage (>1.5 mV), border zone (0.5–1.5 mV), and dense scar areas (<0.5 mV). Results The border zone area had a significant positive correlation with CTO length, as well as a significant negative correlation observed in the preserved voltage region. In the successful PCI patient, the median dense scar area did not change significantly (reported as [median difference: 95% confidence interval]) between baseline and after PCI (0.1 cm2: –2.8 to 2.9). However, the area of the border zone decreased (–10.5 cm2: –16.8 to –4.1) and the preserved voltage area increased significantly (19.2 cm2: 7.7–30.6). In addition, successful PCI was related to slight, but significant, increase in the amplitude of unipolar and bipolar voltage (1.55 mV: 0.88–3.33, 0.23 mV: 0.08–0.36). Conclusions Recanalization of CTO may promote reverse electrical remodeling in the border zone of the left ventricle, without affecting the dense scar tissue.


INTRODUCTION
Chronic total occlusion (CTO) is very common in patients with coronary artery disease and has a reported prevalence of 20-50% among patients referred to the catheterization laboratory with ischemic symptoms. 1 rence of ventricular tachycardia (VT) during follow-up with an adverse impact on long-term mortality. [3][4][5] Several studies have shown that successful recanalization of CTO may significantly reduce angina symptoms, as well as improve the mortality rate and risk of major adverse cardiac events. [6][7][8][9] It has also been reported that successful percutaneous coronary intervention (PCI) for myocardial infarction improves cardiac electric stability but no data were previously published about a potential effect by CTO revascularization on electrical stability. 10,11 In contrast to nonischemic cardiomyopathy, arrhythmias in ischemic cardiomyopathy are frequently related to the endocardial substrate, with fewer patients needing epicardial access to treat VT. 12,13 However, no electrophysiological data have been published regarding the influence of recanalization of CTO on left ventricular electrical remodeling. Therefore, this study was performed to assess the impact of successful PCI for CTO on left ventricular electrical remodeling in patients undergoing paired three-dimensional electroanatomical mapping studies.

Study population
This prospective cohort study was conducted at the Showa University Northern Yokohama Hospital. We prospectively identified 17 consecutive patients undergoing a PCI for de novo native coronary artery CTO at our institution during the period from August 2015 to March 2016. The eligibility criteria are displayed in Figure 1. CTO was defined as a lesion causing complete interruption of blood flow (Thrombolysis In Myocardial Infarction flow grade 0) for an estimated duration of at least 3 months. 14 One patient refused to participate in this study, while the other 16 gave written informed consent and were enrolled.
All participants underwent segmental endocardial electroanatomical mapping of the left ventricle just before PCI and 8-10 months after intervention. Follow-up angiography and electroanatomical mapping were performed at the same timing regardless of the outcome of PCI.

Computed tomography (CT) protocol
All patients underwent coronary CT within 3 months before PCI.
A dual-source CT system (Somatom Definition; Siemens Medical Solutions, Forchheim, Germany) was used with the following settings as described previously: detector collimation 64 × 0.625 mm, table feed 19.7 mm/s, 0.17 helical pitch (beam pitch), rotation time 280 ms, tube current 370 mAs, and voltage 120 kVp. The scanning time ranged from 6 to 8 seconds. Raw scan data were reconstructed using 75% of the RR interval or the applicable optimal phase. A bolus dose of contrast medium (iohexol; Omnipaque, Daiichi-Sankyo Pharmaceutical, Tokyo, Japan) containing 350 mg iodine/mL was injected at a volume of 0.6 mL/kg within 9 seconds. In all patients, a -blocker (bisoprolol fumarate: 2.5 mg) was administrated orally 1 hour before CT scanning and nitroglycerin (0.3 mg) was given just before scanning. Reconstructed CT scans were transferred to a workstation for postprocessing (Ziostation; Amin, Tokyo, Japan). The CTO segment was identified visually in long-axis and short-axis views by using curved multiplanar reformation (cMPR) and comparison with proximal reference segments. The total length of occlusion was measured on cMPR images from the proximal to distal margins of the occluded segment, which was identified by loss of luminal continuity.

Angiography
Quantitative assessment was performed with an automated edge detection system (CASSII; PieMedical, Maastricht, The Netherlands). Images were analyzed by an independent observer who was not involved in the study to avoid bias. The length of each occlusion was measured from the proximal site of obstruction to the distal site of retrograde filling from contralateral collaterals by using a simultaneous bilateral injection technique, from the site where filling of bridging collaterals commenced to that where the distal vessel was clearly visualized, or from the length of the lesion visible after guidewire crossing. Collateral flow was graded according to Rentrop's classification. 15 Other variables such as calcification, tortuosity, bridging collaterals, and stump morphology were assessed according to standard definitions. 16

PCI
The indications for recanalization of CTO lesions were based on current guidelines for myocardial revascularization and stable coronary artery disease. 17  ance. An electrode catheter with a 4-mm tip (NAVISTAR R , Biosense F I G U R E 1 Disposition of the patients. The 16 patients were divided into S-group (n = 13) and U-group (n = 3). CTO = chronic total occlusion; PCI = percutaneous coronary intervention; S-group = patients with successful PCI and no restenosis; U-group = patients with unsuccessful PCI or with reocclusion during the follow-up period Webster) was only used for mapping when the PentaRay R catheter could not do mapping during sinus rhythm without premature ventricular beats. All electrograms were obtained in sinus rhythm and were manually reviewed to exclude noise, artifacts, or premature ventricular contractions.

Electroanatomical mapping
After endocardial mapping, registration of CT data was performed using the CARTO-Merge software. Using the peak-to-peak voltage amplitude on the bipolar electrograms, left ventricular regions were defined as having a preserved voltage (>1.5 mV), a border zone voltage (0.5-1.5 mV), or a dense scar voltage (<0.5 mV). 19,20 Late potentials (LPs) were also defined as low-voltage electrograms (<1 .5 mV) showing a single or multiple continuous delayed electrical components, separated from the local ventricular electrograms by at least 20 ms and recorded after the surface QRS end. 21 In addition, based on the threshold values of unipolar voltage amplitude, 22 left ventricular lesions were also divided into low UNI area (≤8.27 mV) and normal UNI area (> 8.27 mV). Mapping was performed by mainly targeting the low-voltage regions (<1.5 mV), while sufficient sampling was done elsewhere to obtain a fill threshold of 15 mm. All mapping points that were determined to be located >5 mm from the LV endocardial geometry were considered to show poor contact and were excluded from analysis. Areas within 10 mm of the aortic valve and mitral valve were also excluded from assessment. The areas of the three regions defined according to bipolar amplitude were measured by using the standard surface area measurement tool of the CARTO system and the total area was calculated automatically ( Figure 2).

Statistical methods
Results were assessed with the JMP R software (SAS Institute, Cary, NC, USA). Categorical data were expressed as frequencies and were compared with Pearson's 2 test and Fisher's exact test. Continuous data were presented as median (first quartiles, third quar-tiles). Shapiro-Wilk test was used to assess normality. Comparison of normally distributed variables between groups was performed by an independent-sample or paired t-test, as appropriate. Nonnormally distributed variables were compared by using the Wilcoxon matched-pairs signed-rank test for paired replicates. The difference was reported as median difference (95% confidence interval). The association between the surface area of each voltage region on endocardial mapping and the length of the CTO measured by CT or coronary angiography was assessed by univariate linear regression analysis. In all analyses, a probability (P) value of <0.05 was considered to indicate statistical significance.

Ethical considerations
This study was carried out according to the principals of the Declaration of Helsinki and the protocol was approved by the SHOWA University Clinical Research Review Board. All experiments were performed in accordance with relevant guidelines and regulations and patients' records and information were anonymized and deidentified before analysis. Written informed consent to participation was obtained previously from all the included patients. The trial was registered at http://www.umin.ac.jp/ctr/index.htm (trial identifier: UMIN000033618).

RESULTS
Of the 16 patients who consented to participate in this study, the guidewire failed to cross the CTO in one patient. In two of the remaining 15 patients, in-stent occlusion occurred during the followup period. Accordingly, we divided the subjects into two groups: (1) 13 patients with successful PCI and no restenosis (S-group) and (2) three   We also calculated the changes of unipolar and bipolar electrograms in the whole left ventricle (Table 5). Median unipolar and bipolar voltage amplitudes showed a slightly but significant increase in all subjects and the S-group after PCI, while no significant voltage changes were observed in the U-group.

DISCUSSION
In this study, we evaluated the impact of successful recanalization of There are differences among imaging modalities with respect to assessment and reporting of the extent and severity of myocardial ischemia and/or necrosis. 23,24 In patients with acute myocardial infarction, the extent of left ventricular remodeling is directly influenced by the area of myocardium impacted by coronary artery occlusion. 25 In contrast, the low-voltage zone may include a substantial amount  infarct-related artery may cause hypoperfusion around the necrotic zone that impacts the border zone and makes it more prone to ventricular arrhythmia. 5 In patients with previous myocardial infarction, VT often occurs because of a scar-related reentry circuit. 31 In the border zone around the dense scar tissue, clumps of viable cardiomyocytes exist among fibrotic tissue, creating the slow conduction channels that are essential for reentry. 31,32 Further prospective studies will be required to determine whether recanalization of CTO can reduce the incidence of lethal ventricular arrhythmias.

LIMITATIONS
Several limitations of this study should be taken into consideration.
First, it was a single-center study that enrolled a small number of patients. In addition, the U-group included only three patients. However, these data compared the electrical remodeling before and after an intervention without any changes of medication except for clopidogrel. Second, electroanatomic mapping is operator-dependent and may not be fully reproducible, even if performed by the same operator.
If small differences are found in this study, it cannot be excluded that they are at least in part justified by mapping discrepancies. In addition, comparing each region at each ventricular segment might affect the result. However, dividing the segment according to electroanatomical map may be influenced by observer and introduce another bias. Moreover, as the voltage maps were obtained using two types of catheters with different electrode sizes and interelectrode spacing, errors may have been introduced in the detection of low-voltage areas. However, the use of the 4-mm tipped catheter was limited to situations where the multipronged catheter produced frequent ectopic activity. Third, we did not induce ventricular arrhythmia before or after PCI, and we have no data about the relationship between ventricular arrhythmia and reduction of the border zone area. Fourth, the follow-up period was only about 8 months. While it is unclear whether this was long enough to evaluate the electrophysiological changes after PCI, Mohdnazri et al. 37 reported that both FFR and the instantaneous wavefree ratio were significantly increased in the territory of the predominant donor vessel after a follow-up period of 4 months. Finally, the epicardial surface voltage was not measured directly, and we evaluated the unipolar signal amplitude as a surrogate for the epicardial voltage.

CONCLUSIONS
In this study population, the CTO length was not related to the area of the dense scar region, but had positive correlationship with the border zone area. Successful recanalization of a CTO may contribute to reverse electrical remodeling in the border zone of the left ventricular myocardium, but does not affect the dense scar region.