Author + information
- Received September 8, 2016
- Revision received January 2, 2017
- Accepted January 27, 2017
- Published online May 15, 2017.
- Keisuke Satogami, MD,
- Yasushi Ino, MD, PhD∗ (, )
- Takashi Kubo, MD, PhD,
- Takashi Tanimoto, MD, PhD,
- Makoto Orii, MD, PhD,
- Yoshiki Matsuo, MD, PhD,
- Shingo Ota, MD, PhD,
- Tomoyuki Yamaguchi, MD, PhD,
- Yasutsugu Shiono, MD, PhD,
- Kunihiro Shimamura, MD,
- Yosuke Katayama, MD,
- Hiroshi Aoki, MD,
- Tsuyoshi Nishiguchi, MD, PhD,
- Yuichi Ozaki, MD, PhD,
- Takashi Yamano, MD, PhD,
- Takeyoshi Kameyama, MD, PhD,
- Akio Kuroi, MD, PhD,
- Hironori Kitabata, MD, PhD,
- Atsushi Tanaka, MD, PhD,
- Takeshi Hozumi, MD, PhD and
- Takashi Akasaka, MD, PhD
- ↵∗Address for correspondence:
Dr. Yasushi Ino, Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama 641-8510, Japan.
Objectives The aim of the present study was to investigate the association between plaque rupture (PR) assessed by optical coherence tomography (OCT), and the transmural extent of infarction (TEI) assessed by contrast-enhanced cardiac magnetic resonance imaging (CE-CMR) in ST-segment elevation myocardial infarction (STEMI) patients after primary percutaneous coronary intervention (PCI).
Background PR is associated with larger infarct size as assessed by cardiac enzymes in STEMI patients. CE-CMR is a favorable method to assess TEI, which can predict the prognosis of STEMI patients.
Methods First, STEMI patients with primary PCI within 12 h after onset were enrolled and divided into 2 groups according to presence (n = 71) or absence (n = 32) of PR at the culprit lesion as assessed by pre-intervention OCT. CE-CMR was performed at 1 week after primary PCI.
Results The frequency of no-reflow phenomenon (37% vs. 16%; p = 0.032) and distal embolization (24% vs. 6%; p = 0.032) was significantly higher in the rupture group compared with the non-rupture group. TEI grade was significantly greater in the rupture group (28% vs. 15% in grade 3 and 45% vs. 13% in grade 4; p < 0.001). Microvascular obstruction was more frequently seen in the rupture group (39% vs. 19%; p = 0.039). Multivariate analysis identified PR (odds ratio: 6.60, 95% confidence interval: 2.19 to 21.69; p < 0.001) and no statin use before admission (odds ratio: 3.37, 95% confidence interval: 1.06 to 11.19; p = 0.039) as independent predictors of TEI grade 3 or 4.
Conclusions PR as assessed by OCT is associated with greater TEI as assessed by CE-CMR in STEMI patients after primary PCI.
- optical coherence tomography
- plaque rupture
- ST-segment elevation myocardial infarction
- transmural extent of infarction
Previous studies have demonstrated that about 60% to 70% of acute coronary syndrome are caused by plaque rupture (PR), 30% to 40% by plaque erosion (PE), and a few percent by calcified nodule (CN) (1,2). Several studies have demonstrated that ST-segment elevation myocardial infarction (STEMI) caused by PR distinguished by intravascular ultrasound or coronary angioscopy is associated with larger infarct size as assessed by cardiac enzymes compared with that caused by other etiologies such as PE or CN (3,4). However, intravascular ultrasound and coronary angioscopy cannot detect the presence of PR in culprit lesions of some patients with STEMI (5). Optical coherence tomography (OCT) is a high-resolution (approximately 10 to 20 μm) imaging modality. OCT allows us to identify PR, PE, and CN in patients with STEMI (5–7).
Contrast-enhanced cardiac magnetic resonance imaging (CE-CMR) was introduced as the favorable method to assess the transmural extent of infarction (TEI) and the infarct size (8–10). The TEI assessed by CE-CMR can predict the long-term functional recovery of the left ventricle (LV) and the prognosis of patients with STEMI after primary percutaneous coronary intervention (PCI) (8,10,11).
The aim of the present study was to investigate the relationship between the presence of PR as assessed by OCT, and TEI as assessed by CE-CMR in patients with STEMI after primary PCI.
Between September 2011 and March 2014, primary PCI for a de novo lesion in a native coronary artery was performed in 198 STEMI patients. Inclusion criteria were patients ages ≥20 years; ST-segment elevation ≥0.1 mV in 2 or more contiguous leads on a 12-lead electrocardiogram (ECG); elevated myocardial enzymes (serum creatine kinase-myocardial band [CK-MB] fraction levels more than 2 times higher than normal); patients undergoing primary PCI with OCT guidance for a de novo lesion in a native coronary artery within 12 h from the onset of the symptom; and patients undergoing CE-CMR at 1 week after primary PCI. Exclusion criteria were cardiogenic shock, previous myocardial infarction, previous coronary bypass surgery, left main coronary artery lesion, renal insufficiency (serum creatinine >1.5 mg/dl), side branch (>1 mm) occlusion after PCI, no stent implantation, no pre-intervention OCT images (aspiration catheter did not pass through the culprit lesion in 8 patients, and Thrombolysis In Myocardial Infarction [TIMI] flow grade 3 was not obtained despite the passage of aspiration catheter in 5 patients), poor OCT image quality, contraindications to CE-CMR, such as pacemaker, atrial fibrillation, and claustrophobia. We retrospectively enrolled 103 patients with STEMI who underwent pre-intervention OCT, primary PCI with stent, and CE-CMR at 1 week after primary PCI (Figure 1). This study was approved by the Wakayama Medical University Ethics Committee, and written informed consent was obtained from all patients.
OCT imaging and primary PCI
Oral aspirin (200 mg) and intravenous heparin (100 U/kg) were administered before coronary catheterization. Thrombolysis was not performed for any patient. Coronary angiography was carried out in the standard manner. The infarct-related lesion was identified on the basis of the findings of a coronary angiogram as well as an electrocardiogram and transthoracic echocardiogram. Additional intravenous heparin (5,000 U) was administered before primary PCI. In patients with TIMI flow grade ≤2, aspiration thrombectomy was performed with an aspiration catheter (Thrombuster III GR, Kaneka, Osaka, Japan), but pre-dilation by balloon catheter was not allowed before OCT imaging. Intracoronary isosorbide dinitrate (2 to 3 mg) was administered before the OCT procedure. Frequency-domain OCT (FD-OCT) imaging system (C7-XR/ILUMIEN OPTIS, St. Jude Medical, St. Paul, Minnesota) was used in the present study. Following a Z-offset adjustment, a FD-OCT image catheter (Dragonfly/Dragonfly JP/ILUMIEN OPTIS imaging catheter, St. Jude Medical) was advanced beyond the infarct-related lesion over a 0.014-inch conventional angioplasty guidewire. After the catheter placement, pre-heated contrast media at 37°C (Omnipaque 350 Injection, Daiichi Pharmaceutical, Tokyo, Japan) was flushed through the guiding catheter at a rate of 2 to 4 ml/s for approximately 3 to 6 s using an injector pump (Mark V, Medrad, Warrendale, Pennsylvania). When a blood-free image was observed, the FD-OCT imaging core was withdrawn up to 50 mm at a rate of 20 mm/s using the stand-alone electronic control of the pullback motor. FD-OCT images were stored digitally for subsequent analysis. After OCT imaging, PCI was performed using a coronary stent with a conventional technique. Decision making related to the PCI strategy was left to the discretion of the individual PCI operator. The use of a distal protection device was not allowed. All patients received dual antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day) after primary PCI.
Coronary angiography analysis
Quantitative coronary angiographic analysis was performed using a validated automated edge detection algorithm (CAAS-5, Pie Medical, Maastricht, the Netherlands) by experienced investigators (T.Y. [Takashi Yamano] or Y.S.) who were blinded to the clinical information and OCT and CMR findings. The reference vessel diameter, minimal luminal diameter, and percent diameter stenosis were measured in the culprit lesion. Intracoronary thrombus was identified by angiographic haziness, globular filling defect, or total occlusion. The degree of perfusion was evaluated according to TIMI criteria. Collaterals were graded according to Rentrop's classification, with good collateral flow defined as grade 2 or 3. No-reflow phenomenon was defined as TIMI flow grade 0, 1, or 2 without a mechanical obstruction on angiograms after PCI. Distal embolization was defined as a distal filling defect with an abrupt “cutoff” in the main infarct-related artery or one of the peripheral coronary branches, distal to the site of angioplasty. TIMI blush grade was also applied to evaluate myocardial perfusion after PCI (12).
OCT image analysis
All OCT images were analyzed by 2 independent investigators (T.N. and K.S.) who were blinded to the clinical, angiographic, and CMR data. When there was any discordance between the observers, a consensus reading was obtained. OCT images were analyzed using previously validated criteria for plaque characterization (13). Lipid was semiquantified by measuring the lipid arc. When the lipid arc stretched for >90°, the plaque was deemed to be lipid-rich. PR was defined as the presence of fibrous cap discontinuity and a cavity formation in the plaque (5,6,13,14). PE was identified by the presence of attached thrombus overlying an intact and visualized plaque and the absence of fibrous cap disruption, luminal surface irregularity at the culprit lesion in the absence of thrombus, or attenuation of underlying plaque by thrombus without superficial lipid or calcification immediately proximal or distal to the site of thrombus (6). CN was defined by fibrous cap disruption detected over a calcified plaque characterized by protruding calcification, superficial calcium, or the presence of substantive calcium proximal and/or distal to the lesion (6). The culprit lesions that did not meet the aforementioned criteria were classified as others. Calcification was defined as an area with low backscattering signal and a sharp border inside a plaque (6,13). Microchannel was defined as a no-signal tubuloluminal structure without a connection to the vessel lumen recognized on ≥3 consecutive cross sections (6,13). Macrophage accumulation was defined as a high-intensity, signal-rich linear region with sharp attenuation (13). Intracoronary thrombus was defined as a mass attached to the luminal surface or floating within the lumen (5–7,13,14). Thrombus area was measured by planimetry in each frame (0.2 mm), and thrombus volume was calculated with the use of Simpson’s rule (7). Minimum lumen area was defined as the smallest lumen area along the length of the target lesion.
A 12-lead ECG was recorded on admission and 1 h after the primary PCI, at a paper speed of 25 mm/s and an amplification of 10 mm/mV. ST-segment resolution was calculated by the reduction in the sum of the ST-segment elevation in all leads except aVR from the baseline ECG to the 1-h ECG. The ST-segment resolution was defined as a reduction of ≥70% ST-segment elevation after primary PCI (15).
Cardiac enzyme measurements
Blood samples were obtained on admission and serially every 3 h for the first 24 h after primary PCI, and the peak values of CK and CK-MB were determined.
CMR protocol and analysis
CE-CMR was scheduled at 1 week after the primary PCI to assess infarct area, TEI, and LV function. All patients were examined at rest in the supine position with a whole-body 1.5-T magnetic resonance imaging scanner (Intera Achieva, Philips Medical Systems, Best, the Netherlands) equipped with a 5-element cardiac phased-array coil for signal reception. All images were obtained with electrocardiographic gating in contiguous short-axis slices and representative long-axis slices of the LV during repeated breath-holds.
CE-CMR was performed 10 min after intravenous injection of 0.1 mmol/kg gadolinium diethylenetriamine pentaacetic acid. We optimized the inversion time (200 to 300 ms) to nullify healthy myocardium. All analyses were performed by 2 independent observers (T.T. and S.O.) who were blinded to the clinical, angiographic, and OCT findings using an offline workstation (View Forum, Philips, Berlin, Germany). When there was any discordance between the observers, a consensus reading was obtained. Epicardial and endocardial borders were traced in each cine image to obtain LV end-diastolic volume, LV end-systolic volume, and LV ejection fraction. The TEI was graded from 1 to 4 on the basis of the transmural extent of hyperenhanced tissue within each segment: 1 = 1% to 25% of LV wall thickness; 2 = 26% to 50%; 3 = 51% to 75%; and 4 = 76% to 100% (8,10,11). The highest grade among the 16 segments except the apex was defined as the TEI grade of each case. Microvascular obstruction (MVO) was evaluated qualitatively on delayed enhanced images; it was defined as hypodense regions within the hyperenhanced infracted area, and MVO was included in the calculation of total infarct size (8–10). The representative case of each TEI grade and MVO is shown in Figure 2.
All statistical analysis was performed with the statistical software package JMP 10.0 software (SAS Institute, Cary, North Carolina). Results are expressed as mean ± SD for continuous variables. Categorical data are presented as number (%). Continuous variables data were compared by means of the Student t test, and categorical data were compared by the chi-square test or Fisher exact test (if the expected cell value was <5) between 2 groups. Additionally, the standardized differences were used to compare the continuous variables in patient clinical, angiographic, and procedural characteristics. The nonparametric Kruskal-Wallis test was used to test for differences in the TEI grade between 2 groups. Multiple logistic regression analysis was performed to determine independent predictors of TEI grade 3 or 4. The parameters with p < 0.2 in univariate analysis were enrolled: PR, lipid-rich plaque, single-vessel disease, thrombus in angiography, stent-to-artery-ratio, diabetes mellitus, no statin use before admission, and pre-infarction angina. A p value <0.05 was considered statistically significant.
Baseline clinical characteristics
Patients were classified according to the presence or absence of PR as determined by pre-intervention OCT; 71 patients had PR (the rupture group), and 32 did not have PR (the non-rupture group). The non-rupture group consisted of 28 patients with PE, 3 patients with CN, 1 patient with other. Baseline clinical characteristics are summarized in Table 1. There were no significant differences in baseline clinical characteristics except for the higher frequency of pre-infarction angina in the non-rupture group (63% vs. 39%; p = 0.030).
Angiographic findings and procedural characteristics
The angiographic findings and procedural characteristics are shown in Table 2. Quantitative coronary angiographic analysis findings and TIMI flow grade before and after PCI, collateral flow grade ≤2, and myocardial brush grade 0 or 1 were not different between the 2 groups. The frequency of thrombus (82% vs. 59%; p = 0.016), no-reflow phenomenon (37% vs. 16%; p = 0.032) and distal embolization (24% vs. 6%; p = 0.032) was higher in the rupture group compared with the non-rupture group. There were no significant differences in procedural characteristics, stent profiles, and reperfusion time between the 2 groups.
OCT findings are shown in Table 3. The frequency of lipid-rich plaque was significantly higher (93% vs. 56%; p < 0.001), and lipid arc was greater (171 ± 73° vs. 137 ± 67°; p = 0.018) in the rupture group compared with the non-rupture group.
Acute clinical outcomes after primary PCI
The frequency of ST-segment resolution was lower in the rupture group compared with the non-rupture group (32% vs. 56%; p = 0.022). The peak CK (3,755 ± 2,826 IU/l vs. 1,768 ± 1,593 IU/l; p < 0.001) and CK-MB level (328 ± 206 IU/l vs. 180 ± 175 IU/l; p < 0.001) were higher in the rupture group compared with the non-rupture group. The incidence of post-myocardial infarction heart failure during hospitalization tended to be higher in the rupture group compared with the non- rupture group (24% vs. 9%; p = 0.084).
CMR findings are shown in Table 4. LV ejection fraction was significantly lower in the ruptured group compared with the non-rupture group (46 ± 10% vs. 51 ± 8%; p = 0.009). TEI grade was greater in the rupture group (28% vs. 15% in grade 3 and 45% vs. 13% in grade 4; p < 0.001) (Figure 3). Furthermore, the incidence of MVO was higher in the rupture group compared with the non-rupture group (39% vs. 19%; p = 0.039).
The comparing results including CMR findings in the subgroups with and without pre-infarction angina are shown in Table 5. The peak CK (2,678 ± 2,656 IU/l vs. 3,539 ± 2,633 IU/l; p = 0.036) and CK-MB level (245 ± 218 IU/l vs. 314 ± 195 IU/l; p = 0.026) were lower in patients with pre-infarction angina compared with those without it. The incidence of TEI grade 3 or 4 tended to be lower in patients with pre-infarction angina compared with those without it (50% vs. 67%; p = 0.075).
Determinations of TEI grade 3 or 4
Multiple logistic regression analysis for predicting TEI grade 3 or 4 is shown in Table 6. Multivariate analysis confirmed PR (odds ratio: 6.60, 95% confidence interval: 2.19 to 21.69; p = 0.001) and no statin use before admission (odds ratio: 3.37, 95% confidence interval: 1.06 to 11.19; p = 0.039) as independent predictors of TEI grade 3 or 4.
The main findings of the present study were as follows: 1) the incidence of no-reflow phenomenon and distal embolization was higher in the rupture group compared with the non-rupture group; 2) the frequencies of TEI grade 3 or 4 and MVO were higher in the rupture group; and 3) PR and no statin use before admission were independent predictors of TEI grade 3 or 4.
Culprit lesion morphology assessed by OCT
Previous pathological studies showed that about 60% to 70% of acute coronary syndromes was caused by PR, about 30% to 40% by PE, and a small portion by CN (1,2). Previous OCT studies demonstrated that the prevalence of OCT-derived PR and PE at the culprit lesion of acute myocardial infarction (AMI) was about 64% to 73% and 23% to 27%, respectively (5,7,14). In the present study, the prevalence of PR and PE at the culprit lesion was 69% and 27%, which is similar to that of previous pathological and OCT studies. The prevalence of CN in the present study was 3%, which was lower compared with that in previous OCT studies (8%) (6,7). One of these studies demonstrated that serum creatinine levels were higher in patients with CN compared with patients with other classified types of culprit lesion (6). In the present study, patients with renal insufficiency (serum creatinine >1.5 mg/dl) including hemodialysis were excluded. The lower incidence of CN in the present study may be due to the different population being studied.
CE-CMR findings in AMI patients after primary PCI
CE-CMR findings in AMI patients after primary PCI is associated with the prognosis in chronic phase. It is difficult to evaluate true infarct size and residual myocardial viability in early phase after primary PCI by using echocardiography and/or single-photon emission computed tomography because of stunned myocardium. CE-CMR may be more sensitive than echocardiography and single-photon emission computed tomography (8,9). Choi et al. (8) demonstrated that the TEI assessed by CE-CMR in patients within 1 week after the onset of AMI predicts improvement in LV contractile function in chronic phase. They reported that 33% of myocardial segments with 51% to 75% TEI, and only 5% of those with 76% to 100% TEI improved in the chronic state. Other studies demonstrated that the presence of the transmural necrosis defined as myocardial segments with ≥51% TEI in patients with AMI was the powerful predictor of major adverse cardiac events in patients with AMI after reperfusion therapy (10,11).
Moreover, previous studies demonstrated that MVO detected by CE-CMR is correlated with histopathological evidence of severely disturbed microvasculature (16). Nijveldt et al. (17) revealed that MVO was related to adverse LV remodeling and poor LV functional recovery. Another study demonstrated that the presence of MVO was associated with worse prognosis in patients with AMI after primary PCI (11,18).
The major causes of greater TEI grade and/or MVO are distal embolization of thrombi and plaque components migrated by stent implantation (7–10,19). Previous studies reported that ruptured plaque with large necrotic core were associated with a high risk of no-reflow after primary PCI in patients with AMI and plaque content, rather than thrombus, may be the major determinant of microcirculatory damage (3,19). Therefore, identification of culprit lesions that are predisposed to causing distal embolization and/or no-reflow before primary PCI might allow us to predict the occurrence of greater TEI grade and/or MVO.
Prevention of greater TEI grade
The present study demonstrated that the presence of OCT-derived PR at the culprit lesion was associated with larger infarct size, such as not only peak CK, CK-MB, but also the frequency of TEI grade 3 or 4 assessed by CE-CMR. Moreover, the presence of OCT-derived PR was identified as the only independent predictor of TEI grade 3 or 4. Therefore, OCT might be a useful tool for risk stratification in patients with AMI undergoing primary PCI. Furthermore, the prevention of TEI grade 3 or 4 is important to avoid major adverse cardiac events in AMI patients. One potential therapeutic strategy to prevent distal embolization and/or no-reflow by using a distal protection device has been suggested (20,21). Mizote et al. (20) demonstrated that distal embolization and LV dysfunction after primary PCI are more frequent among patients with PR assessed by angioscopy than among those without PR, and distal protection device was useful in improving LV function only in patients with angioscopy-derived ruptured plaque. Although the effectiveness of distal protection devices is inconsistent and routine use of them is not recommended (21), the use in selected patients with OCT-derived PR at the culprit lesion may effectively prevent the occurrence of greater TEI grade. A prospective randomized trial of distal protection devices in STEMI patients with OCT-derived PR is needed.
First, aspiration thrombectomy was performed before OCT imaging in patients with TIMI flow grade ≤2. A thrombectomy catheter might have modified the culprit lesion morphologies. Second, residual thrombus might affect analysis of the plaque behind it. Especially, they might make it difficult to distinguish PR from non-PR. Third, we could not perform CE-CMR before primary PCI. A possibility that myocardial damage may exist before onset of AMI cannot be denied. Finally, this is a retrospective study with a relatively small population size. Therefore, further prospective study with sample size calculation is required to confirm the finding of this study.
PR assessed by OCT is associated with greater transmural extent of infarction as assessed by CE-CMR in patients with STEMI after primary PCI.
WHAT IS KNOWN? PR assessed by intracoronary imaging modalities is associated with larger infarct size as assessed by cardiac enzymes in STEMI patients, compared with other etiologies. CE-CMR is the favorable method to assess TEI, which can predict the prognosis of STEMI patients after primary PCI.
WHAT IS NEW? PR assessed by OCT is associated with greater TEI and MVO as assessed by CE-CMR in STEMI patients after primary PCI, compared with non-PR, including plaque erosion and calcified nodule.
WHAT IS NEXT? The use of a distal protection device in selected patients with OCT-derived PR at the culprit lesion may effectively prevent the occurrence of greater TEI grade and MVO. A prospective randomized study of distal protection device use in STEMI patients with OCT-derived PR is needed.
Dr. Kubo has received lecture fees from St. Jude Medical and Terumo. Dr. Akasaka has received lecture fees and research grants from St. Jude Medical, Terumo, and Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute myocardial infarction
- contrast-enhanced cardiac magnetic resonance imaging
- creatine kinase-myocardial band
- calcified nodule
- frequency-domain optical coherence tomography
- left ventricle/ventricular
- microvascular obstruction
- optical coherence tomography
- percutaneous coronary intervention
- plaque erosion
- plaque rupture
- ST-segment elevation myocardial infarction
- transmural extent of infarction
- Thrombolysis In Myocardial Infarction
- Received September 8, 2016.
- Revision received January 2, 2017.
- Accepted January 27, 2017.
- 2017 American College of Cardiology Foundation
- Virmani R.,
- Kolodgie F.D.,
- Burke A.P.,
- Farb A.,
- Schwartz S.M.
- Davies M.J.
- Kusama I.,
- Hibi K.,
- Kosuge M.,
- et al.
- Kubo T.,
- Imanishi T.,
- Takarada S.,
- et al.
- Jia H.,
- Abtahian F.,
- Aguirre A.D.,
- et al.
- Higuma T.,
- Soeda T.,
- Yamada M.,
- et al.
- Choi K.M.,
- Kim R.J.,
- Gubernikoff G.,
- Vargas J.D.,
- Parker M.,
- Judd R.M.
- Hombach V.,
- Grebe O.,
- Merkle N.,
- et al.
- Bodi V.,
- Sanchis J.,
- Nunez J.,
- et al.
- Merlos P.,
- López-Lereu M.P.,
- Monmeneu J.V.,
- et al.
- Sharma V.,
- Jolly S.S.,
- Hamid T.,
- et al.
- Tearney G.J.,
- Regar E.,
- Akasaka T.,
- et al.,
- International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT)
- Ino Y.,
- Kubo T.,
- Tanaka A.,
- et al.
- Sejersten M.,
- Valeur N.,
- Grande P.,
- Nielsen T.T.
- Judd R.M.,
- Lugo-Olivieri C.H.,
- Arai M.,
- et al.
- Nijveldt R.,
- Beek A.M.,
- Hirsch A.,
- et al.
- Jaffe R.,
- Charron T.,
- Puley G.,
- Dick A.,
- Strauss B.H.
- Kotani J.,
- Nanto S.,
- Mintz G.S.,
- et al.
- Mizote I.,
- Ueda Y.,
- Ohtani T.,
- et al.