Association of Intravascular Ultrasound- and Optical Coherence Tomography-Assessed Coronary Plaque Morphology With Periprocedural Myocardial Injury in Patients With Stable Angina Pectoris

Abstract

Background: Periprocedural myocardial injury (PMI) is not an uncommon complication and is related to adverse cardiac events after percutaneous coronary intervention (PCI). We investigated the predictors of PMI in patients with stable angina pectoris (SAP) on intravascular imaging.

Methods and Results: We enrolled 193 SAP patients who underwent pre-PCI intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Clinical characteristics, lesion morphology, and long-term follow-up data were compared between patients with and without PMI, defined as post-PCI elevation of high-sensitivity cardiac troponin-T. PMI were observed in 79 patients (40.9%). Estimated glomerular filtration rate (odds ratio [OR], 0.973; 95% confidence interval [CI]: 0.950–0.996; P=0.020), ≥2 stents (OR, 3.100; 95% CI: 1.334–7.205; P=0.009), final myocardial blush grade 0–2 (OR, 4.077; 95% CI: 1.295–12.839; P=0.016), and IVUS-identified echo-attenuated plaque (EA; OR, 3.623; 95% CI: 1.700–7.721; P<0.001) and OCT-derived thin-cap fibroatheroma (OCT-TCFA; OR, 3.406; 95% CI: 1.307–8.872; P=0.012) were independent predictors of PMI on multivariate logistic regression analysis. A combination of EA and OCT-TCFA had an 82.4% positive predictive value for PMI. On Cox proportional hazards analysis, PMI was an independent predictor of adverse cardiac events during 1-year follow-up (hazard ratio, 2.984; 95% CI: 1.209–7.361; P=0.018).

Conclusions: Plaque morphology assessment using pre-PCI IVUS and OCT may be useful for predicting PMI in SAP patients. (Circ J 2015; 79: 1944–1953)

Periprocedural myocardial injury (PMI), diagnosed on cardiac biomarker elevation, is not an uncommon complication, and remains a clinical concern for post-percutaneous coronary intervention (PCI) outcome in patients with coronary artery disease.^1–3 PMI can be caused by procedure-related PCI complications, such as distal embolization, side-branch occlusion, coronary dissection, and disrupted collateral flow.^3–5 Several studies have reported that PMI were related to adverse outcome, even in patients with small cardiac biomarker increases and clinically uneventful PCI.^1,2,6 Preprocedural PMI prediction might, therefore, be beneficial for the prognosis of PCI patients.

Editorial p 1891

Previous studies, using intravascular ultrasound (IVUS), have shown that several characteristics of atherosclerotic coronary plaque, such as large plaque burden,^4,7 echo-attenuated plaque (EA),⁸ or plaque with necrotic tissues,⁹ are associated with PMI. Optical coherence tomography (OCT), a newly developed and high-resolution intravascular imaging modality, may enable the classification of vulnerable plaque within coronary lesions.^10,11 OCT-derived thin-cap fibroatheroma (TCFA) or ruptured plaque are also predictive of PMI in patients undergoing elective PCI.^12,13 Recently, several studies have reported that a combination of IVUS and OCT might be useful for assessing lesion characteristics.^14,15 The effectiveness of IVUS-OCT coronary plaque characterization in PMI prediction, however, is undetermined.

We hypothesized that the combined use of OCT and IVUS would allow the optimal evaluation of plaque characteristics as factors related to PMI occurrence. Accordingly, we investigated the relationships between culprit lesion coronary plaque morphology, evaluated on IVUS and OCT, and the occurrence of PMI in patients with stable angina pectoris (SAP) undergoing elective PCI.

Methods

Subjects

We retrospectively reviewed 230 consecutive SAP patients with 230 single-culprit, native, and de novo coronary artery lesions who underwent pre-intervention IVUS and OCT, between June 2011 and October 2013, at Yokosuka Kyosai Hospital, Kanagawa. SAP was defined as a positive stress test for myocardial ischemia and no change in frequency, duration, or intensity of angina symptoms within 6 weeks before PCI. Of the 230 patients, we excluded patients with chronic totally occluded lesions, left main trunk lesions, those treated with rotational atherectomy or distal protection devices, final angiographic evidence of side branch occlusions, coronary dissection or slow-reflow phenomenon (Thrombolysis in Myocardial Infarction [TIMI] flow grade 0–2) after PCI, and insufficient IVUS or OCT quality (Figure S1). Patients with multiple culprit lesions, lesions that could not be crossed with the IVUS and/or OCT catheter before PCI due to heavy calcification or extreme tortuosity, PCI at another coronary site within 1 month, renal insufficiency (creatinine, >3.0 mg/dl) or need for hemodialysis, and accompanying congestive heart failure (CHF) before PCI were also excluded. Thus, 193 patients were included in the study.

The Institutional Review Committee of Yokosuka Kyosai Hospital approved this study, and all patients provided written informed consent.

Laboratory Analysis

Cardiac troponin-T (cTnT) was determined immediately before and after PCI, and at 24 h after PCI, using a high-sensitivity (hs) cTnT assay (Elecsys Troponin T high sensitive assay; Roche Diagnostics, Mannheim, Germany; lower detection limit, 3 ng/L; coefficient of variation <10% at 14 ng/L [99th percentile of reference control group]). PMI was defined as peak cTnT during the 24 h after PCI >70 ng/L (5-fold the 99th percentile of the upper reference limit [URL] in patients with normal baseline level [cTnT <14 ng/L],³ or >5-fold the baseline level if pre-PCI cTnT ≥14 ng/L). Other laboratory data were measured before PCI according to established procedures.

Angiography and Interventional Procedures

Quantitative coronary angiography was performed using CAAS 4.1.1 (Pie Medical Imaging, Maastricht, The Netherlands). Minimal lumen diameter (MLD), reference vessel diameter, diameter stenosis, and lesion length of the culprit lesions were measured, and the acute gain was calculated using the difference between pre- and post-PCI MLD. Coronary flow was assessed according to TIMI flow grade¹⁶ and corrected TIMI frame count.¹⁷ Myocardial perfusion was assessed using myocardial blush grade (MBG).¹⁸ Coronary angiograms were analyzed by 2 experienced observers unaware of the OCT and IVUS findings. All patients were treated with aspirin (100 mg/day) and thienopyridines (ticlopidine 200 mg/day, or clopidogrel 75 mg/day). Before PCI, all patients received i.v. heparin (8,000–10,000 IU) and i.c. nitroglycerin (0.2 mg). The culprit lesion was identified using a combination of coronary angiography, left ventricular (LV) wall motion abnormalities, electrocardiography, angiographic lesion morphology, and scintigraphic evidence of ischemia. Conventional PCI was performed, and all patients had <25% residual stenosis after stent implantation.

IVUS

IVUS was performed before PCI and after i.c. nitroglycerin administration. A 40-MHz rotational IVUS imaging catheter (Boston Scientific, Natick, MA, USA) was automatically retracted at 0.5 mm/s from >10 mm distal to the proximal side (>10 mm proximal or aorto-ostial junction) of the culprit lesion, but before any large side branch. Serial IVUS images were digitized and archived for analysis. Two experienced observers, blinded to patient, angiography and OCT information, analyzed the IVUS images offline (QIvus 2.0; Medis Medical Imaging Systems, Leiden, The Netherlands). If there was discordance between the 2 observers, a consensus diagnosis was obtained with repeated off-line readings. Quantitative measurements and qualitative gray-scale IVUS assessments were performed, as previously recommended.¹⁹ The culprit lesion, on IVUS, was defined as the site with the smallest lumen, and the reference site was selected as the most normal-looking region within 10 mm distal and proximal of the culprit lesion. The cross-sectional areas (CSA) of the external elastic membrane (EEM) and lumen were measured at the lesion and reference sites. Plaque area was calculated using the difference between the lumen CSA and the EEM CSA, and plaque burden was calculated as the plaque area divided by EEM CSA×100 (%). Reference data were calculated as the average of the proximal and distal values. Remodeling index was defined as EEM CSA at the culprit site divided by the reference site EEM CSA. Positive remodeling was defined as remodeling index >1.05. EA was defined as atherosclerotic plaque with ultrasound signal attenuation without very high intensity echo reflectors that involved >90° of the vessel circumference and had a length >1 mm.²⁰ Bright echoes with <90° of acoustic shadowing or size <1 mm were defined as spotty calcifications.

OCT

After IVUS, OCT was carried out before PCI with a time-domain OCT (M3 System; LightLab Imaging, Westford, MA, USA), between June 2011 and December 2011, or a frequency-domain OCT system (C7/C8 system; St. Jude Medical, St. Paul, MN, USA), between January 2012 and October 2013, as previously described.²¹ With the M3 system, an occlusion balloon (Helios; LightLab Imaging) was advanced proximal to the lesion and inflated to 0.3–0.5 atm during image acquisition. The imaging wire was positioned distal to the culprit lesion and then automatically pulled back from the distal to the proximal site at 1.5 mm/s (20 frames/s); lactated Ringer’s solution was continuously infused from the tip of the occlusion balloon. With the C7, C8 system, a 2.7-Fr OCT catheter (Dragonfly; St. Jude Medical) was advanced distal to the lesion, and automatically pulled back at 20 mm/s (100 frames/s; C7) or 36 mm/s (180 frames/s; C8) to the proximal end of the lesions in concordance with blood clearance following injection of contrast media or low-molecular-weight dextran. Using angiography references and landmarks, such as the aorto-ostial junction, side branches, and calcification sites, the image location at the culprit lesion site could be determined and compared with IVUS findings.⁸ Offline analysis was performed using proprietary software (LightLab Imaging). All OCT images were analyzed by 2 independent investigators unaware of the angiography, IVUS, or other clinical data. Discordance between the 2 investigators was resolved by consensus diagnosis with repeated off-line readings. Cross-sectional OCT was analyzed with a 1.0-mm interval. Qualitative and quantitative analyses of plaque morphologies were performed according to previously validated criteria for OCT plaque characterization.^11,22–24 Lipid arc degrees and overlying fibrous cap thickness at the thinnest part were measured in lipidic plaque. Lipid-rich plaque was defined as lipid arc >180°, whereas TCFA was defined as lipid-rich plaque with fibrous cap thickness <70 μm.^8,12,23 Plaque rupture was defined as fibrous cap discontinuity, with cavity formation. In the plaque rupture, the residual fibrous cap was identified as a flap between the lumen and the cavity, and its thickness was measured at the thinnest part;⁸ i.c. thrombus was defined as a mass protruding into the vessel lumen.^12,23 For the calcified content of a plaque, the maximum value was used for subsequent analyses. Calcification thickness that was clearly imaged on OCT was measured up to OCT signal drop-off.²⁵ Calcification arc was also measured on OCT.

Study Endpoints and Follow-up

Clinical complications and outcome during post-PCI follow-up were assessed in all patients. The post-discharge follow-up data were collected at outpatient clinic or through telephone interview. The study endpoints were adverse cardiac events defined as CHF (presence of a third heart sound, Killip class >2, Forrester subset >2, or evidence of radiographic pulmonary congestion), recurrent or new-onset unstable angina pectoris (UAP), non-fatal MI, target vessel revascularization (TVR), or cardiac death.

Statistical Analysis

IBM SPSS Statistics 21.0 (IBM, Armonk, NY, USA) was used for all statistical analyses. Categorical data are expressed as absolute frequency and percentage, and were compared using chi-squared or Fisher’s exact test, as appropriate. Continuous variables are expressed as mean±SD for normally distributed variables or as median (25–75th percentiles) for non-normally distributed variables, and were compared using Student’s t-test or Mann-Whitney U-test, respectively. Intra- and interobserver agreement for qualitative plaque morphology determined on IVUS and OCT were assessed using κ statistics. Multivariate logistic regression analysis (stepwise-forward method) was used to evaluate the relationships between clinical, biochemical, angiographic, IVUS, and OCT parameters, and the occurrence of PMI. To control for multiple comparisons, pairwise tests were performed with each variable. Associated variables with P<0.10 on univariate analysis, were included in the multivariate model. Natural logarithmic transformation was used for regression analysis of non-normally distributed variables. Kaplan-Meier estimates of adverse cardiac event rate distributions after PCI, were compared between patients with and without PMI using the Mantel-Cox test. Cox regression analysis was performed to assess the predictors of adverse cardiac events during follow-up. Hazard ratios (HR) with corresponding 95% confidence intervals (95% CI) were also calculated. Variables associated with adverse cardiac events at the P<0.10 level on univariate analysis were included in multivariate Cox regression analysis. P<0.05 was considered statistically significant.

Results

Baseline and Procedural Characteristics

PMI were observed in 79 (40.9%) of the 193 patients (Table 1). Those with PMI had higher frequency of chronic kidney disease, lower estimated glomerular filtration rate (eGFR), and higher brain natriuretic peptide (BNP) before PCI than those without PMI; no significant differences were seen in other baseline characteristics.

Table 1. Subject Baseline and Procedural Characteristics

	Total (n=193)	With PMI (n=79)	Without PMI (n=114)	P-value
Age (years)	69±9	70±8	68±9	0.15
Male gender	159 (82.4)	61 (77.2)	98 (86.0)	0.12
BMI (kg/m2)	24.3±3.7	24.1±3.8	24.5±3.6	0.50
Current smoker	48 (24.9)	18 (22.8)	30 (26.3)	0.58
Diabetes mellitus	69 (35.8)	27 (34.2)	42 (36.8)	0.70
Hypertension	140 (72.5)	60 (75.9)	80 (70.2)	0.38
Dyslipidemia	114 (59.1)	51 (64.6)	63 (55.3)	0.20
Previous MI	50 (25.9)	22 (27.8)	28 (24.6)	0.61
Previous PCI	104 (53.9)	45 (57.0)	59 (51.8)	0.48
Chronic kidney disease	89 (46.1)	44 (55.7)	45 (39.5)	0.03
Baseline LVEF (%)†	63.3±9.3	63.9±9.2	62.9±9.4	0.47
Medication
Aspirin	193 (100)	79 (100.0)	114 (100.0)	1.00
Thienopyridines	191 (98.9)	78 (98.7)	113 (99.1)	1.00
β-blocker	105 (54.4)	42 (53.2)	63 (55.3)	0.77
Statin	171 (88.6)	68 (86.1)	103 (90.4)	0.36
ACEI or ARB	140 (72.5)	56 (70.9)	84 (73.7)	0.67
Nicorandil	48 (24.9)	20 (25.3)	28 (24.6)	0.91
Sulfonylurea	31 (16.1)	12 (15.2)	19 (16.7)	0.78
Laboratory data before PCI
HDL-C (mg/dl)	43 (36–49)	43 (36–49)	43 (37–51)	0.65
LDL-C (mg/dl)	82 (68–100)	81 (67–101)	82 (68–99)	0.98
Triglyceride (mg/dl)	130 (91–185)	135 (91–191)	126 (92–163)	0.45
Hemoglobin A1c (NGSP) (%)	6.2±1.2	6.0±1.0	6.2±1.1	0.22
eGFR (ml/min/1.73 m2)	62.3±15.1	58.4±14.9	64.9±15.0	0.004
hs-cTnT (ng/L)	10 (6–16)	11 (6–16)	10 (6–17)	0.64
WBC count (109 cells/L)	6.0 (5.0–7.0)	6.1 (5.2–7.6)	5.8 (4.8–6.8)	0.15
hs-CRP (mg/L)	1.1 (0.5–3.1)	1.0 (0.5–2.6)	1.1 (0.4–3.5)	0.86
BNP (pg/ml)	40 (23–71)	51 (26–95)	36 (20–60)	0.03
Angiographic data
LAD/RCA/LCX	95/56/42 (49.2/29.0/21.8)	34/27/18 (43.0/34.2/22.8)	61/29/24 (53.5/25.4/21.1)	0.31
Pre-PCI MLD (mm)	1.0±0.3	0.9±0.3	1.0±0.3	0.24
Pre-PCI RD (mm)	2.9±0.5	2.9±0.5	3.0±0.5	0.62
Lesion length (mm)	21.9±9.5	24.2±10.0	20.3±8.8	0.006
B2/C‡	114 (59.1)	48 (60.8)	66 (57.9)	0.69
Pre-CTFC	18±10	19±11	18±8	0.38
Pre-PCI MBG 0–2	21 (10.9)	9 (11.4)	12 (10.5)	1.00
Post-PCI RD (mm)	3.1±0.5	3.2±0.4	3.1±0.5	0.42
Post-PCI MLD (mm)	2.9±0.4	2.9±0.4	2.9±0.5	0.47
Acute gain (mm)	1.9±0.5	2.0±0.4	1.9±0.5	0.14
DES use	178 (92.2)	76 (96.2)	102 (89.5)	0.11
Direct stenting	10 (5.2)	3 (3.8)	7 (6.1)	0.53
Stent diameter (mm)	3.3±0.4	3.3±0.3	3.3±0.4	0.31
Stent length (mm)	23.4±9.0	25.4±9.3	22.0±8.5	0.01
No. stents ≥2	36 (18.7)	21 (26.6)	15 (13.2)	0.02
Balloon post-dilatation	163 (84.5)	70 (88.6)	93 (81.6)	0.23
Final CTFC	15±7	16±7	15±6	0.42
Final MBG 0–2	22 (11.4)	17 (21.5)	5 (4.4)	<0.001
IVUS data
Reference EEM CSA (mm2)	13.4±4.1	13.6±3.9	13.2±4.2	0.46
Lesion EEM CSA (mm2)	13.6±4.4	14.4±4.1	13.1±4.6	0.045
Lesion plaque area (mm2)	11.2±4.3	12.0±4.0	10.7±4.5	0.04
Lesion plaque burden (%)	80.6±8.0	82.2±6.1	79.5±8.9	0.01
Remodeling index	1.05±0.25	1.09±0.28	1.01±0.22	0.03
Positive remodeling	89 (46.1)	42 (53.2)	47 (41.2)	0.10
EA	55 (28.5)	37 (46.8)	18 (15.8)	<0.001
Spotty calcification <90°	90 (46.6)	44 (55.7)	46 (40.4)	0.04
OCT data
Lipid arc (°)	172±101	197±95	154±102	0.004
Fibrous cap thickness (μm)	209±116	170±105	237±116	<0.001
Calcification arc (°)	132±80	131±81	133±79	0.94
Calcification thickness (μm)	599±268	587±257	608±279	0.69
Lipid-rich plaque	100 (51.8)	51 (64.6)	49 (43.0)	0.003
TCFA	30 (15.5)	22 (27.9)	8 (7.0)	<0.001
Plaque rupture	26 (13.5)	9 (11.4)	17 (14.9)	0.53
Thrombus	32 (16.6)	14 (17.8)	18 (15.8)	0.72
Laboratory data after PCI
Peak cTnT (ng/L)	67 (29–171)	185 (119–360)	34 (19–57)	<0.001

Data given as n (%), mean±SD, or median (IQR). ^†Assessed on echocardiography; ^‡lesion complexity assessed according to the modified classification of the American College of Cardiology/American Heart Association. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; BNP, brain natriuretic peptide; CSA, cross-sectional area; CTFC, corrected TIMI frame count; DES, drug-eluting stent; EA, echo-attenuated plaque; EEM, external elastic membrane; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; hs-cTnT, high-sensitivity cardiac troponin T; IVUS, intravascular ultrasound; LAD, left anterior descending artery; LCX, left circumflex artery; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MBG, myocardial blush grade; MI, myocardial infarction; MLD, minimal lumen diameter; NGSP, National Glycohemoglobin Standardization Program; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; PMI, periprocedural myocardial injury; RCA, right coronary artery; RD, reference diameter; TCFA, thin cap fibroatheroma; TIMI, Thrombolysis in Myocardial Infarction; WBC, white blood cell.

The lesions in patients with PMI were angiographically longer than those in patients without PMI. IVUS-determined lesion EEM CSA, lesion plaque area, % plaque burden, and remodeling index were significantly greater, and the frequency of EA and spotty calcifications significantly higher in PMI lesions. On OCT, larger lipid arc, thinner fibrous cap, higher ratio of lipid-rich plaque, and TCFA were seen at the culprit site in PMI lesions compared with non-PMI lesions. Change (∆, post-PCI minus pre-PCI) in hs-cTnT significantly correlated with fibrous cap thickness but not with lipid arc (Figure S2). Longer stent length, more stents, and higher ratio of final MBG 0–2 were also observed in PMI lesions compared with non-PMI lesions.

Factors Associated With PMI

Table 2 lists the results of the univariate and multivariate logistic regression analyses for the occurrence of PMI. On multivariate analysis, eGFR, ≥2 stents, final MBG 0–2, EA, and OCT-TCFA were independently associated with PMI.

Table 2. Factors Associated With PMI

	OR	95% CI	P-value
Univariate logistic regression analysis
eGFR (per 1-ml/min/1.73 m2 increment)	0.971	0.951–0.991	0.005
BNP (per 10-fold increment)	1.750	0.906–3.379	0.096
Lesion length (per 1-mm increment)	1.045	1.012–1.079	0.007
No. stents ≥2	2.390	1.143–4.997	0.021
Final MBG 0–2	5.977	2.103–16.99	0.0008
Lesion plaque burden (per 1% increment)	1.049	1.007–1.093	0.023
Remodeling index	3.937	1.181–13.130	0.026
EA	4.698	2.405–9.181	<0.001
IVUS-spotty calcification	1.858	1.040–3.321	0.036
OCT-TCFA	5.114	2.141–12.218	<0.001
Multivariate logistic regression analysis
eGFR (per 1-ml/min/1.73 m2 increment)	0.973	0.950–0.996	0.020
No. stents ≥2	3.100	1.334–7.205	0.009
Final MBG 0–2	4.077	1.295–12.839	0.016
EA	3.623	1.700–7.721	<0.001
OCT-TCFA	3.406	1.307–8.872	0.012

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Plaque Characteristics of EA

In lesions with EA, the EEM CSA, plaque area and burden, and the remodeling index were significantly greater, and the frequency of positive remodeling and spotty calcifications significantly higher than in those without EA. OCT showed greater lipid arcs, thinner fibrous cap, smaller calcification arcs, and thinner calcification in lesions with EA than in those without. The frequencies of OCT-identified TCFA, plaque ruptures, and thrombi were also significantly higher in lesions with EA (Table 3; Figure 1). The combination of EA and OCT-TCFA at the culprit site had a higher predictive value for PMI than each variable, alone (Figure 2).

Table 3. Characteristics of Echo-Attenuated Plaque

	Total (n=193)	With EA (n=55)	Without EA (n=138)	P-value
IVUS data
Reference EEM CSA (mm2)	13.4±4.1	14.1±4.3	13.1±3.9	0.16
Lesion EEM CSA (mm2)	13.6±4.4	15.9±4.8	12.7±3.9	<0.001
Lesion plaque area (mm2)	11.2±4.3	13.6±4.8	10.3±3.7	<0.001
Lesion plaque burden (%)	80.6±8.0	84.2±6.5	79.2±8.1	<0.001
Remodeling index	1.05±0.25	1.18±0.29	0.99±0.22	<0.001
Positive remodeling	89 (46.1)	40 (72.7)	49 (35.5)	<0.001
Spotty calcification	90 (46.6)	44 (80.0)	46 (33.3)	<0.001
OCT data
Lipid arc (°)	172±101	222±79	152±102	<0.001
Thinnest fibrous cap thickness (μm)	209±116	157±100	230±116	<0.001
Calcification arc (°)	132±80	89±42	147±83	<0.001
Calcification thickness (μm)	599±268	483±193	633±280	0.004
Lipid rich plaque	100 (51.8)	39 (70.9)	61 (44.2)	<0.001
TCFA	30 (15.5)	17 (30.9)	13 (9.4)	<0.001
Plaque rupture	26 (13.5)	12 (21.8)	14 (10.1)	0.03
Thrombus	32 (16.6)	16 (29.1)	16 (11.6)	0.003

Data given as n (%) or mean±SD. Abbreviations as in Table 1.

Figure 1.

Optical coherence tomography findings in echo-attenuated plaque: (A) lipid-rich plaque with thick fibrous cap; (B) thin-cap fibroatheroma; (C–E) plaque rupture and thrombi; and (F) small calcifications.

Figure 2.

Event rate of periprocedural myocardial injury (PMI) for each plaque characteristic. The combination of echo-attenuated plaque (EA) and thin-cap fibroatheroma (TCFA) had higher predictive value for PMI than each on its own.

Clinical Course After PCI

During a median follow-up period of 14 months (range, 10–20 months), post-PCI adverse cardiac events occurred in 23 patients (11.9%), and were significantly more frequent in patients with PMI than in those without (Table 4). Early events (30-day follow-up) in patients with PMI included 3 cases of CHF (2 occurring within 2 days and 1 occurring 20 days after PCI). Within the next 5 months, 1 cardiac death, 2 cases of UAP, 2 MI, and 3 TVR occurred in patients with PMI; 2 TVR were accompanied by UAP and 1 TVR was accompanied by MI. During follow-up months 7–12, 1 CHF event and 4 TVR occurred in patients with PMI. Very late events (>1-year follow-up) in patients with PMI included 2 CHF events and 1 MI. Five of the 6 patients with PMI who had CHF during follow-up, had LV or renal dysfunction at baseline. Fourteen of the 23 adverse cardiac events (60.9%) that occurred during follow-up were related to the original culprit lesions. In patients with PMI, event-free survival was significantly worse than in those without PMI (Figure 3). On multivariate Cox regression analysis that included body mass index, systemic pre-PCI BNP, PMI, and angiographic acute gain, stent length, and final inflation pressure, PMI remained as an independent predictor of adverse cardiac events during follow-up (Table 5).

Table 4. Clinical Outcome During Follow-up

	Total (n=193)	With PMI (n=79)	Without PMI (n=114)	P-value
Congestive heart failure	7 (3.6)	6 (7.6)	1 (0.9)	0.02
Unstable angina	3 (1.6)	2 (2.5)	1 (0.9)	0.57
Non-fatal MI	4 (2.1)	3 (3.8)	1 (0.9)	0.31
Ischemic TVR	13 (6.7)	7 (8.9)	6 (5.3)	0.39
Cardiac death	1 (0.5)	1 (1.3)	0 (0.0)	0.41
Cumulative adverse cardiac events†	23 (11.9)	16 (20.3)	7 (6.1)	0.006

Data given as n (%). ^†Congestive heart failure, unstable angina, non-fatal MI, ischemic TVR, or cardiac death. TVR, target vessel revascularization. Other abbreviations as in Table 1.

Figure 3.

Cumulative adverse cardiac event rate distribution during post-percutaneous coronary intervention follow-up was significantly different between patients with and without periprocedural myocardial injury (PMI).

Table 5. Factors Associated With Adverse Cardiac Events After PCI

	HR	95% CI	P-value
Univariate Cox regression analysis
Age (per 1-year increment)	1.010	0.960–1.062	0.712
Male gender	0.822	0.306–2.208	0.700
BMI (per 1-kg/m2 increment)	0.892	0.792–1.005	0.062
Current smoker	1.700	0.723–3.997	0.226
Diabetes mellitus	0.614	0.243–1.550	0.304
Hypertension	1.036	0.410–2.617	0.941
Dyslipidemia	1.034	0.450–2.380	0.937
Previous MI	1.546	0.658–3.630	0.320
Chronic kidney disease	0.772	0.336–1.777	0.545
Baseline LVEF (per 1% increment)	1.018	0.971–1.068	0.459
Statin use	1.296	0.306–5.489	0.726
ACEI or ARB use	1.952	0.667–5.709	0.224
HDL-C (per 1-mg/dl increment)	1.008	0.975–1.041	0.655
LDL-C (per 1-mg/dl increment)	0.995	0.979–1.011	0.546
Hemoglobin A1c (per 1% increment)	0.883	0.573–1.358	0.572
eGFR (per 1-ml/min/1.73 m2 increment)	1.012	0.985–1.039	0.399
Pre-PCI cTnT (per 10-fold increment)	1.249	0.411–3.795	0.696
Pre-PCI hs-CRP (per 10-fold increment)	0.702	0.341–1.446	0.340
Pre-PCI BNP (per 10-fold increment)	2.138	0.918–4.979	0.080
PMI	3.380	1.396–8.184	0.007
LAD lesion	1.909	0.830–4.394	0.130
Lesion length (per 1-mm increment)	1.026	0.988–1.065	0.192
B2/C	1.522	0.644–3.600	0.341
Post-PCI MLD (per 1-mm increment)	0.638	0.241–1.689	0.368
Acute gain (per 1-mm increment)	0.463	0.194–1.105	0.084
DES use	0.608	0.181–2.043	0.423
No. stents ≥2	1.445	0.572–3.652	0.439
Stent diameter (per 1-mm increment)	0.917	0.542–1.552	0.748
Stent length (per 1-mm increment)	1.037	0.997–1.079	0.074
Final inflation pressure (per 1-atm increment)	0.877	0.759–1.013	0.075
Final MBG 0–2	1.464	0.499–4.300	0.490
Lesion EEM CSA (per 1-mm2 increment)	0.962	0.874–1.060	0.439
Lesion plaque burden (per 1% increment)	1.011	0.959–1.067	0.685
Remodeling index	1.080	0.237–4.911	0.921
EA	0.859	0.340–2.168	0.748
IVUS spotty calcification	0.490	0.202–1.186	0.116
OCT lipid rich plaque	1.396	0.606–3.216	0.435
OCT-TCFA	1.402	0.521–3.775	0.506
Multivariate Cox regression analysis
PMI	2.984	1.209–7.361	0.018

Abbreviations as in Tables 1,2.

Intra- and Interobserver Agreement

There was very good intra- and interobserver agreement regarding the identification of EA (intraobserver variability, κ=0.95; interobserver variability, κ=0.87), OCT-lipid rich plaque (κ=0.92 and 0.84), TCFA (κ=0.89 and 0.82), plaque rupture (κ=0.91 and 0.86), and thrombus (κ=0.92 and 0.84).

Discussion

The present study showed that pre-PCI coronary plaque characteristics detected on IVUS and OCT were associated with PMI in SAP patients. On multivariate analysis, EA and OCT-TCFA at the culprit site were independent predictors of PMI after elective stenting, as well as eGFR, number of stents, and final MBG 0–2, and the combination of EA and OCT-TCFA had higher predictive value for PMI than either on its own. Further, PMI, defined as elevation of hs-cTnT, was associated with worse outcome in SAP patients during follow-up than in those without PMI.

Previous studies have reported that EA were more common in patients with acute coronary syndrome (ACS) than in SAP patients, and were an independent risk factor for poor post-PCI outcome, especially in ACS patients.^8,20,26,27 Our previous study identified a relationship between EA and poor post-PCI outcome in both SAP and ACS patients.²⁰ The clinical significance of EA in SAP patients, however, remains unclear. The present study showed that EA are not uncommon and might be independently associated with PMI in SAP patients.

Several OCT studies, mostly involving ACS patients, have focused on TCFA as an independent factor for poor post-PCI outcome.^12,13,28 TCFA can easily be destroyed during PCI and may induce outflow of active tissue factors, such as thrombogenic components, into the coronary circulation, thereby causing microvascular impairment and distal embolization, resulting in PMI.^12,28 In SAP patients, a recent study identified the lipid tissue arc as an independent predictor of PMI.²⁹ The present OCT data showed that unstable plaque such as TCFA, plaque rupture, and thrombus is not uncommon, and that TCFA might be independently related to PMI in SAP patients. This may be related to the enrollment of SAP patients with elevated baseline cTnT that may have been clinically silent, but with more vulnerable lesions than in those with normal baseline cTnT.³⁰

OCT-identified EA instability is linked to TCFA with large lipid arcs and thin fibrous caps,¹² consistent with the present results. In a recent histopathological analysis of autopsy specimens, EA were indicative of either a fibroatheroma with a large necrotic core or pathological intimal thickness with a large lipid pool.³¹ Our previous analysis of retrieved atherectomy specimens also found that lesions with EA had more lipid-rich plaque with macrophage infiltration, cholesterol cleft, and microcalcification than those without EA.²⁰ The present OCT data showed that lesions with EA, compared with those without EA, had quantitatively larger lipid arc or thinner fibrous cap, and, further, smaller calcification arcs or thinner calcification. Spotty calcification is significantly associated with vulnerable plaque,^31,32 and identified these features as predictors of PMI in SAP patients.³³ EA may result from a combination of these unstable and fragile plaque components, leading to distal embolization, and resulting in myocardial injury after PCI even in SAP patients. In contrast, not all lesions with EA may have unstable plaque with TCFA (Figure 1). In the present study, the frequency of EA accompanied by lipid-rich plaque and TCFA were lower than in previous studies involving ACS patients.^8,20,26,27 The present multivariate analysis identified both EA and OCT-TCFA as independent PMI predictors in SAP patients, helping explain their greater combined PMI predictive value.

An hs-cTnT assay was used to demonstrate an association between small myocardial injury after elective stenting and poor outcome during a 1-year post-PCI follow-up in SAP patients; the mechanism of this association remains unclear. Lee et al described periprocedural myocardial damage during PCI as leading to LV dysfunction or electric instability.¹² In the present study, patients with PMI had higher a frequency of cumulative cardiac events, especially CHF, during follow-up, than those without PMI. Kusumoto et al found a significant correlation between hs-cTnT and echocardiographic indices reflecting left and right ventricular function.³⁴ Baseline LV systolic functioning in the present patients was similar between those with and without PMI, but the higher frequency of CHF during follow-up in patients with PMI might be due to impaired LV diastolic relaxation. In the present study, the majority of CHF patients during follow-up after PMI, had LV or renal dysfunction at baseline. The occurrence of CHF in patients with PMI might be associated not only with periprocedural myocardial damage, but also with baseline patient characteristics such as LV or renal dysfunction. PMI, even if the degree was small or mild, would influence the occurrence of CHF in patient with LV or renal dysfunction at baseline. On multivariate analysis, eGFR was independently associated with PMI. Renal dysfunction was associated with progressive LV diastolic dysfunction.³⁵ We speculate that LV or renal dysfunction could be potential risk factors for PMI as well as long-term adverse outcome. Also, approximately 40% of cardiac events were associated with the original non-culprit lesions in the present study. The present and previous studies have shown that PMI might be due to distal embolization from large amounts of destroyed and unstable atherosclerotic plaque after PCI.^{4,7–9,12,13} cTnT has also been reported to correlate with total coronary plaque burden in SAP patients.³¹ We speculate that elevated cTnT after PCI may also reflect the instability and severity of the total coronary atherosclerosis.

IVUS and OCT can each provide beneficial i.c. information; each also has disadvantages, for example, IVUS has limited plaque characterization and resolution, and OCT has poor tissue penetration.^36,37 This study demonstrated that the combined use of both modalities, before PCI, might allow more accurate identification of high-risk plaque characteristics predictive of PMI, linked to poor, post-PCI long-term outcome. When unstable plaque characteristics, such as EA, OCT-TCFA, or both, are observed before PCI, aggressive drug therapy, thrombectomy, or distal protection devices should be considered to prevent or reduce distal embolization and PMI in SAP patients.

Study Limitations

This was a small, single-center, retrospective study and selection bias may have occurred, for example, exclusion of lesions that were difficult to observe on IVUS, OCT, or both. The present frequency of PMI may be relatively high, but is consistent with previous studies.^9,13 PMI was defined using hs-cTnT, which might contribute to a higher frequency of PMI than that using standard troponin assay. The presence of both EA and TCFA had a high predictive value for PMI, also, the frequency of PMI in the absence of those plaques might not be low, but was not contradictory to previous studies.^9,13 We originally defined PMI as peak post-PCI cTnT >5-fold the baseline in patients with baseline cTnT ≥normal range, whereas PMI in patients with normal baseline cTnT were identified according to the “universal definition”.³ Median peak post-PCI hs-cTnT in lesions with PMI was 185ng/L, >10-fold the 99th percentile of the URL. Clinical implications of post-PCI myocardial damage and the optimal threshold of hs-cTnT for PMI remain controversial.³⁸ The present study, however, has demonstrated a significant relationship between PMI and poor outcome during follow-up. Also, the frequency of adverse cardiac events during follow-up increased according to the grade of hs-cTnT elevation (Figure S3). Thus, the present PMI definition may be useful for prediction of post-PCI outcome in SAP patients. The present study included patients with elevated baseline cTnT, which might influence post-PCI outcome. Univariate and multivariate analysis, however, showed no significant relationships between baseline cTnT and occurrence of PMI or cardiac events during follow-up. A direct relationship between IVUS and OCT plaque morphology, and adverse cardiac events could not be shown in the present study, which might be due to multifactorial mechanism of adverse outcome after PMI. EA or OCT-TCFA, however, were identified as independent predictors for occurrence of PMI, linked to adverse outcome. Pre-PCI assessment of plaque morphology may be useful in risk stratification of SAP patients undergoing elective PCI. Two OCT systems (frequency-domain and time-domain OCT system) were used in the present study. The time-domain OCT system had slower pullback speed and lower frame rate than frequency-domain OCT, but there were no significant differences in the characterization of lesion morphology between the 2 systems in the present study. The evaluation of plaque components under i.c. thrombi is sometimes difficult, but the frequency and amount of thrombi were relatively low because the present patients had SAP. Thus, the existence of thrombi may not be of importance to the conclusions. Finally, we did not evaluate plaque volume, which is an important factor for distal embolization; both EA and OCT-TCFA, however, are related to positive remodeling and large plaque burden,^{8,12,20,26,27} possibly leading to the high predictive value of these plaque components for PMI.

Conclusions

There is a significant association between EA, OCT-TCFA, and PMI. Assessment of plaque morphology using pre-PCI IVUS and OCT may be useful in risk stratification of SAP patients undergoing elective PCI.

Disclosures

The authors report no conflicts of interest with respect to this manuscript.

Supplementary Files

Supplementary File 1

Figure S1. Study flow chart.

Figure S2. Relationship between cap thickness and lipid arc, and change in high-sensitivity cardiac troponin-T (hs-cTnT).

Figure S3. Frequency of adverse cardiac events during follow-up vs. grade of high-sensitivity cardiac troponin T (hs-cTnT) elevation.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-14-1375

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