Circulation: Cardiovascular Imaging

ORIGINAL ARTICLE

Culprit Lesion Morphology of Rapidly Progressive

and Extensive Anterior-Wall ST-Segment
Elevation Myocardial Infarction
Kozo Okada , MD; Kiyoshi Hibi , MD; Shinnosuke Kikuchi, MD; Hidekuni Kirigaya, MD; Yohei Hanajima, MD;
Ryosuke Sato, MD; Hidefumi Nakahashi , MD; Yugo Minamimoto, MD; Yasushi Matsuzawa, MD; Nobuhiko Maejima, MD;
Noriaki Iwahashi , MD; Masami Kosuge, MD; Toshiaki Ebina, MD; Kouichi Tamura, MD; Kazuo Kimura, MD

BACKGROUND: Rapidly progressive, extensive myocardial injury/infarction (RPEMI) beyond the concept of wave-front phenomenon
can be observed even when achieving timely reperfusion; however, the pathogenesis of RPEMI remains unknown. This
retrospective study investigated clinical and lesion characteristics of RPEMI, focusing on culprit-lesion morphology (CLM).

METHODS: Among patients with extensive anterior-wall ST-segment elevation myocardial infarction due to proximal left anterior
descending artery lesions who had reperfusion within 3 hours of symptom onset, 60 patients undergoing both intravascular
ultrasound and cardiac magnetic resonance imaging were enrolled. Myocardial injury/infarction before reperfusion therapy
was assessed by QRS scores at hospitalization electrocardiogram, and the extent of myocardial injury/infarction was
evaluated by cardiac magnetic resonance imaging, which measured area at risk, infarct size, myocardial salvage index,
microvascular obstruction, and left ventricular ejection fraction. RPEMI was defined as lower left ventricular ejection fraction
(less median value) with microvascular obstruction.
Downloaded from http://ahajournals.org by on November 27, 2022

RESULTS: Despite comparable onset-to-door and onset-to-reperfusion times and area at risk, patients with RPEMI showed higher
QRS scores at hospitalization (5 [4.3–6] versus 3 [2–4], P<0.001) and infarct size (26.5±9.1 versus 20.4±10.5%, P=0.04), and a
tendency toward lower myocardial salvage index (0.27±0.14 versus 0.36±0.20, P=0.10) compared with those without. Patients
with versus without RPEMI more frequently observed specific CLM on intravascular ultrasound, characterized by the combination
of vulnerable plaques, plaque ruptures, and/or large thrombi. When stratified by CLM-score composed of these 3 criteria, higher
CLM-scores were or tended to be associated with higher QRS scores and incidence of RPEMI. In multivariate analyses including
no-reflow phenomenon and final coronary-flow deterioration, increased CLM-score (≥2) was independently associated with high
QRS scores and RPEMI (odd ratio 11.25 [95% CI, 2.43–52.00]; P=0.002).
CONCLUSIONS: Vulnerable CLM was a consistent determinant of advanced myocardial injury/infarction both before and after
reperfusion therapy and may play a pivotal role in the development of RPEMI.

Key Words:  heart failure ◼ plaque rupture ◼ vulnerable plaque

See Editorial by Derimay and Rioufol

E
arly reperfusion therapy with percutaneous coronary
intervention (PCI) and associated major advances in
medical treatments and emergency-care systems
have substantially improved the prognosis of ST-segment
elevation myocardial infarction (STEMI).1,2 However, in the
clinical setting, a certain fraction of patients with STEMI
suffered from rapidly progressive, extensive myocardial
injury/infarction (RPEMI) despite achieving clinically

 
Correspondence to: Kozo Okada, MD, PhD, Division of Cardiology, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama City 232-0024,
Japan. Email kokada2@yokohama-cu.ac.jp
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.122.014497.
For Sources of Funding and Disclosures, see page 821.
© 2022 American Heart Association, Inc.
Circulation: Cardiovascular Imaging is available at www.ahajournals.org/journal/circimaging

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 812

 Okada et al
CLINICAL PERSPECTIVE
The present study systematically revealed that rap-
idly progressive, extensive myocardial injury/infarction
(RPEMI) could be observed in a certain fraction of
ST-segment elevation myocardial infarction (STEMI)
despite achieving timely reperfusion (≤3 hours of the
onset), and specific culprit-lesion morphology-score,
composed of 3 intravascular ultrasound criteria, (1)
vulnerable plaques, (2) significant plaque ruptures,
and (3) large thrombi, was an independent determi-
nant of RPEMI. Patients with RPEMI were already
at the advanced stage of STEMI before reperfusion
therapy, which could not be explained by the time-
dependent ischemic process (wavefront phenom-
enon theory) and limited the beneficial effects of early
reperfusion therapy. Although the exact mechanism of
RPEMI and associated medical treatments will need
further investigations, the present study suggests
that once vulnerable plaque significantly ruptures, it
is difficult to prevent the development of RPEMI and
may highlight the importance of early detection of
vulnerable plaques followed by intensive plaque sta-
bilization for reducing future risks for acute coronary
syndrome and RPEMI. The present study provides a
unique opportunity to reconsider the pathogenesis
of RPEMI, which might be the next focus for further
improving clinical outcomes of STEMI.
Downloaded from http://ahajournals.org by on November 27, 2022
ideal onset-to-reperfusion time (≤2–3 hours),2,3 which
may partially contribute to the fact that mortality rate of
STEMI still remains significant and virtually unchanged
over the past decade.4,5 In this context, previous stud-
ies of patients with STEMI have importantly reported that
the extent of myocardial damage before reperfusion, as
determined by QRS scores or Q-waves at hospitalization
ECG could vary between patients even with similar pre-
sentation time, and advanced myocardial damage could
be observed even in patients with early hospitalization
time (≤2 hours).6–9 Previous work from our institution also
found higher numbers of Q-wave leads at hospitalization
ECG in anterior-wall STEMI patients with versus without
plaque rupture among patients with reperfusion within
2 hours of the onset.10 Although myocardial ischemic/
reperfusion injury is a complex process including vari-
ous local and systemic factors,11 these findings suggest
possible associations between CLM and the progression
status of STEMI, as well as the development of RPEMI.
However, there have been limited data in this regard.
As RPEMI has immense impacts on heart failure and
sudden cardiac death due to postinfarct left ventricular
dysfunction even after surviving the index STEMI,12 bet-
ter understanding of such associations may contribute
to further improving clinical outcomes of STEMI. There-
fore, the aim of this study was for the first time to com-
prehensively explore clinical and lesion characteristics
Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497
Impact of Culprit-Lesion Morphology on RPEMI
Nonstandard Abbreviations and Acronyms
AAR area at risk
ACE-I angiotensin-converting enzyme inhibitor
ACS acute coronary syndrome
AHA American Heart Association
ARB angiotensin II receptor blocker
AUC-CK area under the curve for CK
concentrations
BMI body mass index
CK creatine kinase
CLM culprit-lesion morphology
CMR cardiac magnetic resonance imaging
HDL-C high-density lipoprotein cholesterol
hs-CRP high-sensitive C-reactive protein
IABP intra-aortic balloon pumping
IRB institutional review board
IS infarct size
IVUS intravascular ultrasound
LAD left anterior descending artery
LDL-C low-density lipoprotein cholesterol
LVEF left ventricular ejection fraction
MI myocardial injury/infarction
MSI myocardial salvage index
MVO microvascular obstruction
OCT optical coherence tomography
PCI percutaneous coronary intervention
PCPS percutaneous cardiopulmonary support
RCA right coronary artery
RPEMI rapidly progressive, extensive myocar-
dial injury/infarction
STEMI ST-segment elevation myocardial
infarction
TIMI Thrombolysis in Myocardial Infarction
VSA vasospastic angina
WBC white blood cell
of RPEMI in patients with a first extensive anterior-wall
STEMI, focusing especially on underlying CLM.
METHODS
The authors declare that all supporting data are available within
the article.
Study Population
This was a retrospective study performed at Yokohama City
University Medical Center. Between January 2013 and June
2021, patients with a first anterior-wall STEMI due to involve-
ment of the proximal left anterior descending artery segment
(American Heart Association [AHA] classification 6)10 who
showed thrombolysis in myocardial infarction (TIMI) flow grade
November 2022 813
 Okada et al Impact of Culprit-Lesion Morphology on RPEMI
Downloaded from http://ahajournals.org by on November 27, 2022

Figure 1. Patient flow chart.

AHA indicates American Heart Association; CMR, cardiac magnetic resonance imaging; CTO, chronic total occlusion; LAD, left anterior
descending artery; PCI, percutaneous coronary intervention; PCPS, percutaneous cardiopulmonary support; RCA, right coronary artery;
STEMI, ST-segment elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction; and VSA, vasospastic angina.

0 or 1 on initial angiography and then had reperfusion or recan-
alization (TIMI 2 or 3) by primary PCI within 3 hours after symp-
tom onset were screened. Among them, 60 patients scanned
with cardiac magnetic resonance imaging (CMR) were enrolled
(Figure 1). STEMI was defined as the presence of anginal
symptoms (>30 minutes) associated with ST-segment eleva-
tion of at least 0.1 mV in 2 or more contiguous leads, and a
rise in cardiac-specific troponin I values. Patients with coronary
artery bypass grafting or chronic total occlusion of right coro-
nary artery or left circumflex artery with potential collateral from
left anterior descending artery, patients treated with percutane-
ous cardiopulmonary support, patients who died immediately
after primary PCI, or patients with STEMI due to nonath-
erosclerotic causes were excluded. The study protocol was
approved by the institutional review board (IRB) at Yokohama
City University Medical Center, and waiver of written informed
consent was approved by the IRB because of the retrospective
nature of the study. The present study followed the Declaration
of Helsinki and the ethical standards of the responsible com-
mittee on human experimentation.
RPEMI and Associated Myocardial Damage
The degrees of myocardial damage were evaluated by QRS
scores at hospitalization ECG, area under the curve for creatine
kinase concentrations in arbitrary units over the initial 72
hours10 and CMR. QRS score is a well-established, weighted,
quantitative index of myocardial damage that incorporates not
only the number of Q-waves but also increased Q-wave width
and decreased R-wave amplitude and width, both of which
are markers of severe myocardial injury. Higher QRS scores
at hospitalization imply broader transmural myocardial dam-
age due to myocardial ischemia before reperfusion therapy.6,7
CMR was performed at 9.5 [7–12] days after admission using
a 1.5-T MAGNETOM Avanto (Siemens Healthcare) to assess
myocardial damage including all ischemia, reperfusion, and pro-
cedure-related injuries. As previously described,13 CMR images
were analyzed using Q-MASS MR 7.5 (Medis, Netherlands) to
measure infarct size (IS), area at risk (AAR), myocardial sal-
vage index ([AAR-IS]/AAR), microvascular obstruction (MVO),
and left ventricular ejection fraction (LVEF).5,13,14 RPEMI was
defined as low LVEF (less median value) with MVO because
both low LVEF (indexes reflecting all degrees of AAR, IS, and
myocardial salvage index) and MVO (indicators of severe myo-
cardial injury/infarction [MI]) are powerful predictors of poor
prognosis after STEMI.5,14
Reperfusion injury was defined as with ≥2 of the following
variables: re-elevation of ST-segment, worsening chest pain,
and ventricular arrhythmia during reperfusion.15 No-reflow phe-
nomenon was defined as postprocedural TIMI flow grade ≤2

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 814

 Okada et al
in the absence of mechanical obstruction.10 Distal emboliza-
tion was defined as a distal filling defect with an abrupt cut-off
in one of the peripheral coronary branches of the left anterior
descending artery. As factors associated with ischemic precon-
ditioning, pre-infarction angina, defined as the presence of typi-
cal chest pain within 48 hours before the onset, and retrograde
collateral flow (Rentrop grade) were assessed.6
Intracoronary Imaging
In our daily practice, primary PCI was performed with intracoro-
nary imaging guidance (intravascular ultrasound [IVUS] with or
without optical coherence tomography [OCT]). After intracoro-
nary injection of 2 to 3 mg of isosorbide dinitrate, intracoronary
imaging was performed in a standard manner using commer-
cially available imaging systems with automated pullback. All
patients received aspirin (200 mg) orally and Japanese stan-
dard loading dose of 20 mg prasugrel or 300 mg clopidogrel
and intravenous heparin (5000–10 000 units) before primary
PCI. Periprocedural intravenous heparin was administered to
maintain an activated clotting time ≥250 seconds. OCT images
were analyzed in 40 patients due to no OCT procedure (n=8),
no preprocedural OCT images (n=5), missing OCT images
(n=4), and unanalyzable OCT images owing to inadequate
blood removal (n=3).
CLM around minimum lumen area sites with significant
plaque burden and/or plaque rupture (ie, culprit-lesions sites)
was evaluated offline on preprocedure IVUS and OCT images
before balloon dilation or stent implantation by 2 experienced
cardiologists blinded to clinical, angiographic, and CMR data.
Thrombus aspiration was performed before intracoronary
Downloaded from http://ahajournals.org by on November 27, 2022
imaging as necessary. CLM included lipid-rich plaque (≥75%
of the plaque was less bright than adventitia), ultrasound-sig-
nal attenuation (absence of ultrasound signal behind plaque
that was either hypoechoic or isoechoic to the reference
adventitia but contained no bright calcium), plaque rupture,
and large amounts of thrombi (thrombi continuously occupy-
ing more than half of lumen area around culprit-lesion sites)
on IVUS images; lipid arc, plaque rupture, and red- or white-
thrombus dominancy on OCT images.10,16,17 Vulnerable plaque
was defined as lipid-rich plaque with ultrasound-signal attenu-
ation arc >1 quadrant (>90 degrees).18 Because of the limited
resolution of IVUS during STEMI, IVUS findings were allowed
to be appropriately modified by referring to OCT findings as
necessary if patients underwent both IVUS and OCT imaging.
To evaluate associations between CLM and the extent of MI in
detail, culprit-lesion was stratified by CLM-score composed of
3 IVUS criteria: first, having vulnerable plaque as a substrate of
vulnerability; second, IVUS-derived plaque rupture as a trigger
of the release of plaque debris from the disrupted plaque; and
third, large amounts of thrombi as a thrombus burden and 1
point was assigned for each criterion.
Statistical Analysis
Statistical analyses were performed with JMP Pro 16 (SAS
Institute Inc., Cary, NC). Data were expressed as mean±SD
or median with an interquartile range for continuous variables,
and as percentages for categorical variables. With respect to
continuous values, the unpaired Student t test was used to
compare the means between 2 groups, and 1-way analysis of
Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497
Impact of Culprit-Lesion Morphology on RPEMI
variance was used to compare the means among 3 or more
groups. Wilcoxon rank-sum test was used for the comparison
of 2 independent groups of nonparametric data. With respect
to categorical comparisons, Fisher exact test was used when
there was at least 1 cell in the contingency table of the
expected frequencies below 5, and a χ2 test was used for the
other cases. Associations between continuous variables were
investigated using linear regression analysis. Logistic regres-
sion analysis was performed to identify factors associated
with high QRS scores (≥5)6 at hospitalization and RPEMI.
Variables with a P-value of ≤0.10 on univariate analysis were
entered into the multivariate analysis. Gender variables were
defined as male 0, and female 1. Associated odds ratio with
95% CI were assessed. A P-value <0.05 was considered sta-
tistically significant.
RESULTS
Various Progression Statuses of STEMI
Table 1 summarizes clinical and lesion characteris-
tics. The median onset-to-door time (time from symp-
tom onset to hospital arrival) and onset-to-reperfusion
time (ie, total ischemic time) were 56 (45–72) and 107
(89–120) minutes. Troponin I showed no significant
(or slight) elevation at hospitalization, indicating that all
patients presented at the early phase of STEMI. In lin-
ear regression analyses, there was no significant cor-
relation between onset-to-door time and QRS score at
hospitalization, nor between onset-to-reperfusion time
and IS, and their scatter plots were widespread, revealing
various progression statuses of MI and the presence of
RPEMI (Figure 2).
Clinical and Lesion Characteristics: RPEMI
Versus Non-RPEMI
Clinical characteristics were comparable between
patients with and without RPEMI, except for worse final
TIMI flow grade with higher incidences of no-reflow
phenomenon and tendencies toward higher rates of
multivessel disease and worse Killip class in patients
with RPEMI (Table 1). Despite similar onset-to-door
and onset-to-reperfusion times and AAR, patients with
RPEMI showed significantly higher QRS scores at hos-
pitalization and subsequent area under the curve for cre-
atine kinase concentrations and IS compared with those
without (Table 1). In IVUS analysis of culprit-lesion sites,
patients with RPEMI more frequently observed vulner-
able plaques, plaque ruptures, large amounts of thrombi,
and increased CLM-scores than those without (Table 1).
In contrast, patients without RPEMI observed less vulner-
able (mixed) plaques with no significant plaque ruptures
nor large thrombi. Similar trends, as well as significantly
higher percentages of red-thrombus-dominant thrombi,
were seen in patients with versus without RPEMI in OCT
analysis (Table 1).
November 2022 815
 Okada et al Impact of Culprit-Lesion Morphology on RPEMI

Table 1.  Clinical and Lesion Characteristics

Variables All (n=60) RPEMI (n=17) Non-RPEMI (n=43) P value

Age, y 63±12 66±11 62±12 0.31
Male, % 86.7 94.1 83.7 0.42
BMI, kg/mm2 25.1 (22.5–26.7) 24.5 (22.9–25.5) 25.3 (22.2–27.3) 0.44
Coronary risk factors, %
  Current or former smoker 76.7 82.4 74.4 0.74
 Hypertension 58.3 52.9 60.5 0.60
 Dyslipidemia 61.7 47.1 67.4 0.15
 Diabetes 25.0 29.4 23.3 0.74
Medications before admission, %
  Antiplatelet drugs 11.7 17.7 9.3 0.39
 Statin 15.0 11.8 16.3 1.00
 ACEI/ARB 23.3 23.5 23.3 1.00
  Beta blocker 5.0 5.9 4.7 1.00
  Oral anti-diabetic drugs 1.7 0 2.3 1.00
 Insulin 0 0 0 …
Multivessel disease, % 20.0 35.3 14.0 0.08
Pre-infarction angina, % 41.7 29.4 46.5 0.22
Killip class ≥2, % 33.3 47.1 27.9 0.16
Onset-to-presentation time, min 56 (45–72) 67 (42–88) 54 (45–72) 0.29
Onset-to-reperfusion time, min 107 (89–120) 101 (95–144) 108 (87–119) 0.49
QRS score at hospitalization 4 (3–5) 5 (4.3–6) 3 (2–4) <0.001

Reperfusion injury, % 51.7 64.7 46.5 0.20

Laboratory findings
  WBC on admission, μL 9270 (7900–11 600) 8860 (7855–12 055) 9720 (8175–11 633) 0.51
Downloaded from http://ahajournals.org by on November 27, 2022

  hs-CRP on admission, mg/dL 0.135 (0.071–0.270) 0.120 (0.062–0.257) 0.135 (0.077–0.275) 0.66
  BS on admission, mg/dL 152 (131–172) 154 (143–176) 150 (128–174) 0.61
  Hemoglobin A1c on admission, % 5.8 (5.5–6.2) 5.9 (5.6–6.2) 5.8 (5.5–6.1) 0.58
  Triglycerides on admission, mg/dL 135 (93–227) 128 (88–235) 142 (91–218) 0.86
  HDL-C on admission, mg/dL 43 (37–55) 43 (36–57) 44 (38–54) 0.54
  LDL-C on admission, mg/dL 127 (101–146) 129 (113–138) 126 (101–148) 0.82
  Troponin I on admission, ng/mL 0.10 (0.03–0.90) 0.19 (0.04–1.18) 0.09 (0.03–0.90) 0.39
  CK on admission, IU/L 105 (86–174) 113 (88–173) 103 (84–181) 0.62
  CK-MB on admission, IU/L 12 (9–19) 11 (9–17) 12 (9–19) 0.75
  Peak CK, IU/L 3814 (2685–5264) 5667 (4277–6409) 3114 (2149–4304) <0.001

  Peak CK-MB, IU/L 332 (229–483) 483 (422–564) 264 (217–401) <0.001

  AUC-CK, arbitrary units 100 644 130 877 87 763 <0.001

(75 388–13 0585) (104 481–167 591) (56 934–12 4355)
CMR findings
  AAR, % 32.8±13.1 36.4±11.5 31.4±13.5 0.19
  IS, % 22.1±10.4 26.5±9.1 20.4±10.5 0.04
 MSI 0.33±0.19 0.27±0.14 0.36±0.20 0.10
  MVO, % 50.0 100 30.2 <0.001

  LVEF, % 38.9±10.2 30.7±5.2 42.2±9.9 <0.001

Angiographic findings
  Modified APPROACH score 44.5 (42.1–44.5) 44.5 (41.3–44.5) 44.5 (44.5–47.8) 0.27
  Collateral flow of Rentrop ≥1, % 42.3 (22/52) 50.0 (7/14) 39.5 (15/38) 0.50
  Distal embolization, % 15.0 23.5 11.6 0.26
  No reflow during PCI, % 23.3 52.9 11.6 0.002

(Continued )

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 816

 Okada et al Impact of Culprit-Lesion Morphology on RPEMI

Table 1. Continued

Variables All (n=60) RPEMI (n=17) Non-RPEMI (n=43) P value

  Final TIMI flow grade 3, % 85.0 64.7 93.0 0.01
Procedure profiles
  Fibrinolysis, % 1.7 0 2.3 1.00
  Thrombus aspiration, % 61.7 70.6 58.1 0.37
  Distal protection, % 1.7 0 2.3 1.00
  IABP, % 3.3 5.9 2.3 0.49
IVUS findings
  IVUS performed, n 60 17 43 …
  IVUS analyzed, n 60 17 43 …
  Vulnerable plaque, % 28.3 52.9 18.6 0.01
  Plaque rupture, % 35.0 70.6 20.9 <0.001

  Large amounts of thrombi, % 41.7 76.5 27.9 <0.001

 CLM-score 1 (0–2) 2 (1–3) 0 (0–1) <0.001

OCT findings
  OCT performed, n 52 14 38 …
  OCT analyzed, n 40 10 30 …
  Lipid arc ≥2 quadrats, % 33.3 50.0 27.6 0.25
  Plaque rupture, % 27.5 50.0 20.0 0.10
  Red-thrombus-dominant, % 35.0 70.0 23.3 0.02

Values are number (n), percentage (%), mean±SD, or median (interquartile range).
AAR indicates area at risk; ACEI, angiotensin-converting enzyme inhibitor; APPROACH score, the Alberta Provincial Project for Outcome
Assessment in Coronary Heart Disease;33 ARB, angiotensin II receptor blocker; AUC-CK, area under the curve for CK concentration; BS, blood
sugar; BMI, body mass index; CK, creatine kinase; CK-MB, creatine kinase muscle brain; CLM, culprit-lesion morphology; CMR, cardiac magnetic
resonance imaging; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitive C-reactive protein; IABP, intra-aortic balloon pumping;
IS, infarct size; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MSI, myocardial
Downloaded from http://ahajournals.org by on November 27, 2022

salvage index; MVO, microvascular obstruction; OCT, optical coherence tomography; RPEMI, rapidly progressive, extensive myocardial injury/
infarction; TIMI, thrombolysis in myocardial infarction; and WBC, white blood cell.
P values for RPEMI versus Non-RPEMI. Categorical comparisons were performed using χ2 test for hypertension, dyslipidemia, pre-infarction
angina, Killip class ≥2, reperfusion injury, thrombus aspiration, collateral flow, and plaque rupture and large amounts of thrombi by IVUS, and
Fisher exact test for the others.

Impact of CLM on RPEMI
When stratified by CLM-score, higher or trends for higher
CLM-scores were associated with higher QRS scores at
hospitalization (before reperfusion therapy), area under
the curve for creatine kinase concentrations, IS and per-
centages of MVO and RPEMI, and lower myocardial sal-
vage index and LVEF, albeit comparable onset-to-door and
onset-to-reperfusion times and AAR among the groups
(Table 2). Notably, despite comparable onset-to-door and
onset-to-reperfusion times, patients with higher CLM-
score (≥2) demonstrated significantly higher QRS scores
(5 [3–6] versus 4 [2–4], P=0.001) and more severe myo-
cardial damage compared with those with lower CLM-
score (<2; Figure 3). Consistent results were confirmed
in the sensitivity analyses limited to patients with no ret-
rograde collateral flow (n=30), those with negative tropo-
nin I level (n=21), those with reperfusion within 2 hours
of the onset (n=47), and samples from different periods
(n=29 for before 2017, and n=31 for after 2017; Table
S1). Receiver operating characteristics curve analysis
identified the optimal cut-off value of CLM-score as 2 for
predicting RPEMI (Figure 4), and in multivariate analyses,
a higher CLM-score (≥2) was a consistent determinant
of both high QRS scores (≥5) at hospitalization (odds
ratio, 15.19 [95% CI, 3.32–69.60]; P<0.001) and RPEMI
(Table 3), even when adding gender variable in the model.
No-Reflow Phenomenon
No-reflow phenomenon tended to relate to RPEMI in the
multivariate analysis (Table 3). Patients with versus with-
out no-reflow phenomenon achieved less final TIMI flow
grade 3 (42.9% versus 97.8%, P<0.001) and more fre-
quently observed large amounts of thrombi (71.4% versus
32.6%, P=0.01) and CLM-score 3 (28.6% versus 6.5%,
P=0.045). Patients with versus without no-reflow phe-
nomenon also observed borderline statistical differences
of plaque rupture (57.1% versus 28.3%, P=0.06) and
higher CLM-score (≥2; 57.1% versus 26.1%, P=0.05).
DISCUSSION
Limited Effect of Early Reperfusion on
Preventing RPEMI
The current reperfusion strategy is primarily derived
from the concept of time-dependent ischemic process

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 817

 Okada et al Impact of Culprit-Lesion Morphology on RPEMI

Figure 2. Various progression statuses of ST-segment elevation myocardial infarction (STEMI).

There was no correlation between onset-to-door time and QRS score nor between onset-to-reperfusion time and infarct size, showing wide
scatter plots. CMR indicates cardiac magnetic resonance imaging.

(wavefront phenomenon) beginning from endocar-
dium to epicardium with increasing duration of coro-
nary occlusions and severity of ischemia.1,5 Based on
the concept, coronary occlusion lasting particularly
≤2 to 3 hours generally results in smaller MI with
mainly subendocardial infarcts than the ischemic
AAR because some epicardial rim of viable tissue is
Downloaded from http://ahajournals.org by on November 27, 2022
supports the concept and identified that the majority
of patients without RPEMI showed relatively smaller
IS with preserved LVEF than the expected AAR of
extensive anterior-wall STEMI, possibly because of
the beneficial effect of early reperfusion. In contrast,
once vulnerable plaque ruptures, it might be difficult
to prevent the development of RPEMI by early reper-

spared.3 Multiple studies have repeatedly confirmed
the concept by demonstrating strong associations
between time to treatment, the extent of myocardial
salvage, and reduction in mortality, as well as a strik-
ing benefit of reperfusion therapy obtained within the
first 2 to 3 hours of onset.2,3 The present study also
fusion therapy alone. Indeed, despite early (around
1 hour) hospitalization time, patients with RPEMI
already observed high QRS scores at hospitalization,
which could not be explained only by the wavefront
phenomenon and speculated that the evolutionary sta-
tus of MI was in an advanced stage before reperfusion

Table 2.  Extent of MI Stratified by CLM-Score

CLM-score composed of 3 IVUS criteria

Variables 0 (n=24) 1 (n=16) 2 (n=13) 3 (n=7) P value

Onset-to-door time, min 59 (46–70) 54 (45–88) 50 (36–72) 68 (56–86) 0.81
Onset-to-reperfusion time, min 109 (89–119) 102 (92–144) 94 (81–127) 112 (101–138) 0.75
Killip class ≥2, % 29.2 12.5 53.9 57.1 0.049
QRS score at hospitalization 3 (2–4) 4 (3–4.8) 5 (3-6) 6 (5–7) <0.001

AUC-CK, arbitrary units 76 524 98 507 129 709 170 420 <0.001
(54 111–107 189) (86 434–122 601) (104 023–148 349) (157 210–181 119)
CMR findings
  AAR, % 30.4±13.7 30.9±11.6 37.4±14.0 36.7±11.9 0.35
  IS, % 18.4±10.2 21.4±11.6 26.4±6.4 28.4±10.8 0.045
 MSI 0.40±0.17 0.34±0.24 0.26±0.12 0.23±0.13 0.08
  MVO, % 25.0 56.3 61.5 100 <0.001

  LVEF, % 42.8±9.7 41.3±11.4 32.0±6.4 33.1±6.6 0.004

 RPEMI 4.2 25.0 46.2 85.7 <0.001

AAR indicates area at risk; AUC-CK, area under the curve for creatine kinase concentration; CLM, culprit-lesion morphology; CMR, cardiac
magnetic resonance imaging; IS, infarct size; IVUS, intravascular ultrasound; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MSI,
myocardial salvage index; MVO, microvascular obstruction; and RPEMI, rapidly progressive, extensive myocardial injury/infarction.

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 818

 Okada et al Impact of Culprit-Lesion Morphology on RPEMI

Figure 3. Cardiac magnetic resonance (CMR) findings: Higher versus lower culprit-lesion morphology (CLM)-score.
Despite comparable onset-to-door (60 [41–72] vs 56 [45–80] min, P=0.74) and onset-to-reperfusion (108 [84–131] vs 107 [92–120] min,
P=0.94) times, patients with higher versus lower CLM-score had larger infarct size (IS) and higher incidences of microvascular obstruction
(MVO) and rapidly progressive‚ extensive myocardial injury/infarction (RPEMI) and lower myocardial salvage index (MSI) and left ventricular
ejection fraction (LVEF). AAR indicates area at risk.

therapy in patients with RPEMI,6,7 and thereby they
received the limited effects of early reperfusion. Previ-
ous studies support this speculation and have shown
that high QRS scores (Q-waves) can also be seen at
the early presentation of STEMI (≤2 hours) and are
Downloaded from http://ahajournals.org by on November 27, 2022
resultant larger IS than nonruptured plaques.10,16,22–24
The present study extended these studies and dem-
onstrated that the combinations of vulnerable culprit-
lesion features were also associated with myocardial
damage before reperfusion therapy and might deter-

strongly associated with large IS, unsuccessful reper-
fusion, and poor prognosis.6–9 Although total ischemic
time remains a major therapeutic target for reducing
IS, the present study may suggest another possible
time-independent mechanism beyond timely reperfu-
sion for the pathogenesis of RPEMI and highlight the
importance of early detection of vulnerable plaques
followed by intensive plaque stabilization for reducing
future risks for ACS as well as RPEMI.
Possible Mechanisms of RPEMI
The present study revealed a close link between spe-
cific CLM (vulnerable plaques, plaque ruptures, and/
or large thrombi) and RPEMI. Although these culprit-
lesion characteristics inherently relate to each other,
previous clinical and histopathological studies have
repeatedly shown that vulnerable plaques are associ-
ated with large necrotic core, macrophage-infiltration
and inflammatory cytokines, oxidative stress, and acti-
vated coagulation and tissue factors, and are identified
as important determinants of spontaneous plaque rup-
ture and subsequent thrombus formation.18–22 Ruptured
plaques have also been related to larger necrotic-core
and red thrombi, higher numbers of lipid depositions
with foam cells, and greater incidence of no-reflow
phenomenon due to distal embolization, and the
mine the immediate fate of myocardium at risk (ie,
RPEMI). Indeed, contrary to RPEMI, patients without
RPEMI often observed mixed plaques (heterogeneous
layers of lipid, fibrotic, and/or calcified contents) in the
absence of plaque rupture or large/red thrombi (sug-
gestive of healed plaque disruption or erosion pat-
tern).25 A past pathological study reported that almost
half thrombi overlying plaque ruptures had no evidence
of healing, while more than 85% of thrombi overlying
plaque erosions showed late stages of healing, char-
acterized by inflammatory-cell degradation, infiltration
of smooth muscle cells, proteoglycan deposition, and
platelet and fibrin layering.26 It was also reported that
plaque healing process promotes evolution to a more
fibrous, stable plaque, often accompanied by progres-
sive lumen loss with stepwise stenotic progression, and
can lead to ACS without significant plaque disruption
and thrombi.25 Although the exact mechanism remains
a matter of speculation, the present and previous stud-
ies’ results could offer 1 possible mechanism beyond
successful reperfusion that determine the develop-
ment of RPEMI: aside from wavefront time-dependent
myocardial necrosis, spontaneous distal emboliza-
tion of ruptured vulnerable plaque components and
thrombi may directly and/or indirectly injure the myo-
cardium by rapidly inducing local inflammation, oxida-
tive stress, interstitial edema, and MVO as in the case

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 819

 Okada et al Impact of Culprit-Lesion Morphology on RPEMI
Downloaded from http://ahajournals.org by on November 27, 2022

Figure 4. Receiver operating characteristics (ROC) curve analysis.

ROC curve analysis identified the optimal cut-off value of culprit-lesion morphology (CLM)-score as 2, and the highest positive predictive value
(PPV) of CLM-score as 3 for predicting rapidly progressive, extensive myocardial injury/infarction (RPEMI). NPV indicates negative predictive
value.

of reperfusion injury, and enhance patchy myocardial
necrosis, leading to RPEMI (Figure 5).11,27–29 Multiple
controversial reports may support this bold hypothesis
by showing that the efficacy of treatment drugs target-
ing ischemia-reperfusion injury was primarily observed
under animal studies of coronary artery ligation model
based on wavefront phenomenon theory, but it was
limited in in-vivo human coronary arteries,15,30,31 and
indicate the possible importance of underlying CLM in
determining the degrees of myocardial injuries, which
warrants future investigations.
Study Limitations
Several limitations should be noted. First, this was a
hypothesis-generating, single-center, retrospective
analysis with relatively small sample size. The present
findings need to be confirmed in prospective studies
with predefined endpoints in a larger population. Sec-
ond, total ischemic time was defined using patient-
reported symptom onset. Although previous studies
have pointed out the limitation of historical timing,6,8
the present study observed that troponin I levels were
low and did not differ between patients with and with-
out RPEMI and confirmed consistent results in the
subanalysis limited to patients with no troponin I eleva-
tion, suggesting its small impact on our results. Third,
the present study was conducted with conventional
grayscale IVUS with qualitative 2-dimensional analy-
sis, and OCT analysis was performed only in 67% of
the patients. Volumetric analysis with detailed assess-
ments of plaque vulnerability using advanced IVUS
techniques and/or OCT might be more informative.
Fourth, thrombus aspiration was performed in 61.7%
of patients before intracoronary imaging. Although
the frequency of thrombus aspiration was similar in
patients with and without RPEMI, the inhomogeneity
of patients regarding the use of thrombus aspiration
and the potential differences in the effectiveness of
this technique might have influenced the quantifica-
tion of thrombus. Fifth, RPEMI was associated with
large/red thrombi and no-reflow phenomenon, while it

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 820

 Okada et al Impact of Culprit-Lesion Morphology on RPEMI

Table 3.  Factors Associated With RPEMI

Univariate analysis Multivariate analysis

Variables Odds ratio (95% CI) P value Odds ratio (95% CI) P value
Age, y 1.03 (0.98–1.08) 0.30
Female sex 0.32 (0.04–2.83) 0.31
BMI, kg/m 2
0.91 (0.77–1.07) 0.26
Current or former smoker 1.60 (0.39–6.65) 0.52
Hypertension 0.74 (0.24–2.28) 0.59
Dyslipidemia 0.43 (0.14–1.35) 0.15
Diabetes 1.38 (0.39–4.85) 0.62
Multivessel disease 3.36 (0.90–12.55) 0.07 4.09 (0.73–23.06) 0.11
Statin before admission 0.69 (0.13–3.69) 0.66
Pre-infarction angina 0.48 (0.14–1.60) 0.23
Onset-to-door time, min 1.01 (0.99–1.03) 0.24
Onset-to-reperfusion time, min 1.01 (0.99–1.03) 0.36
WBC, μL 1.00 (1.00–1.00) 0.66
hs-CRP, mg/dL 0.52 (0.10–2.75) 0.44
Blood sugar, mg/dL 1.00 (0.99–1.01) 0.91
Hemoglobin A1c, % 1.29 (0.60–2.78) 0.52
TG, mg/dL 1.00 (0.99–1.00) 0.54
HDL-C, mg/dL 0.98 (0.93–1.03) 0.41
LDL-C, mg/dL 1.00 (0.98–1.02) 0.96
Reperfusion injury 2.11 (0.66–6.73) 0.21
No collateral flow (Rentrop grade 0) 0.65 (0.19–2.24) 0.50
Distal embolization 2.34 (0.54–10.05) 0.25
No-reflow phenomenon 8.55 (2.25–32.42) 0.002 5.46 (0.84–35.43) 0.08
Downloaded from http://ahajournals.org by on November 27, 2022

Final TIMI flow grade ≤2 7.27 (1.56–33.86) 0.01 1.01 (0.11–8.87) 1.00
Vulnerable plaque* 4.92 (1.45–16.73) 0.01
Plaque rupture* 9.07 (2.53–32.48) <0.001

Large amounts of thrombi* 8.40 (2.28–30.92) 0.001

CLM-score* 4.35 (2.02–9.40) <0.001

CLM-score ≥2* 10.5 (2.87–38.36) <0.001 11.25 (2.43–52.00) 0.002

BMI indicates body mass index; CLM, culprit-lesion morphology; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-
sensitive C-reactive protein; LDL-C, low-density lipoprotein cholesterol; RPEMI, rapidly progressive, extensive myocardial injury/
infarction; TG, triglycerides; TIMI, thrombosis in myocardial infarction; and WBC, white blood cell.
*Only CLM-score ≥2 was entered into the multivariate analysis.

remains unknown whether treatments targeting them,
such as glycoprotein IIb/IIIa inhibitors32 and distal
protection, could reduce the risk of RPEMI. Finally,
underlying mechanisms of association between spe-
cific CLM and RPEMI remain unclear, which warrants
further investigations in well-designed histopathologi-
cal and clinical studies.
to address the exact mechanisms of RPEMI and associ-
ated treatment options to reduce the risk of RPEMI.
ARTICLE INFORMATION
Received May 25, 2022; accepted October 9, 2022.
Affiliation
Division of Cardiology, Yokohama City University Medical Center, Japan

Conclusions Sources of Funding

None.
Despite achieving timely reperfusion, rapidly progressive
and extensive MI (RPEMI) can develop in a certain fraction Disclosures
of STEMI. Specific CLM, characterized by the combination None.

of vulnerable plaques, plaque ruptures, and large thrombi, Supplemental Material

was associated with RPEMI. Further studies are warranted Table S1

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 821

 Okada et al Impact of Culprit-Lesion Morphology on RPEMI
Downloaded from http://ahajournals.org by on November 27, 2022

Figure 5. Representative cases of rapidly progressive, extensive myocardial injury/infarction (RPEMI) and non-RPEMI.
Case 1 represents RPEMI, and Case 2 and 3 represent non-RPEMI. Case 3 is one of the cases that appeared to receive the maximum
benefit of early reperfusion therapy. Initial coronary angiography revealed TIMI flow grade 1 in RPEMI (A) and TIMI flow grade 0 in non-
RPEMI (F, K). Onset-to-door and onset-to-reperfusion times and AAR were comparable between RPEMI and non-RPEMI (especially,
between Cases 1 and 2), while door-to-guidewire time was numerically shorter in RPEMI than in non-RPEMI. RPEMI had 2 times
higher QRS scores at hospitalization than non-RPEMI, suffered from no-reflow phenomena due to distal embolization during PCI, and
could not achieve TIMI flow grade 3 (Case 1: C). In contrast, non-RPEMI (both Cases 2 and 3) easily and rapidly achieved reperfusion
by simply crossing the guidewire through the culprit lesions. Compared with non-RPEMI, RPEMI showed higher CLM-scores (B,
G, L) with greater extents of MI. CMR identified that RPEMI had extensive transmural necrosis with concomitant MVO in the broad
anteroseptal wall and low LVEF (Case 1: D, E) while non-RPEMI showed subendocardial necrosis without MVO in the anteroseptal
wall (Case 2: I, J) and the apex (Case 3: N, O) and more preserved LVEF. AAR indicates area at risk; AUC-CK, area under the curve
for CK concentration; CK, creatine kinase; CLM, culprit-lesion morphology; CMR, cardiac magnetic resonance imaging; IS, infarct
size; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MSI, myocardial salvage index; MVO, microvascular obstruction;
RPEMI, rapidly progressive, extensive myocardial injury/infarction; and TIMI, thrombolysis in myocardial infarction.

2. Shiomi H, Nakagawa Y, Morimoto T, Furukawa Y, Nakano A, Shirai S,

REFERENCES
1. Gerber BL. Risk area, infarct size, and the exposure of the wavefront phe-
nomenon of myocardial necrosis in humans. Eur Heart J. 2007;28:1670–
1672. doi: 10.1093/eurheartj/ehm213
Taniguchi R, Yamaji K, Nagao K, Suyama T, et al. Association of onset to
balloon and door to balloon time with long term clinical outcome in patients
with ST elevation acute myocardial infarction having primary percutane-
ous coronary intervention: observational study. BMJ. 2012;344:e3257. doi:
10.1136/bmj.e3257

Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497 November 2022 822

 Okada et al
3. Gershlick AH, Banning AP, Myat A, Verheugt FWA, Gersh BJ. Reperfusion
therapy for STEMI: is there still a role for thrombolysis in the era of primary
percutaneous coronary intervention?. Lancet. 2013;382:624–632. doi:
10.1016/S0140-6736(13)61454-3
4. Menees DS, Peterson ED, Wang Y, Curtis JP, Messenger JC, Rumsfeld
JS, Gurm HS. Door-to-balloon time and mortality among patients under-
going primary PCI. N Engl J Med. 2013;369:901–909. doi: 10.1056/
NEJMoa1208200
5. Greulich S, Mayr A, Gloekler S, Seitz A, Birkmeier S,
Schäufele T, Bekeredjian R, Zuern CS, Seizer P, Geisler T, et al. Time-
dependent myocardial necrosis in patients with ST-segment–elevation
myocardial infarction without angiographic collateral flow visualized by
cardiac magnetic resonance imaging: results from the multicenter STEMI-
SCAR project. J Am Heart Assoc. 2019;8:e012429. doi: 10.1161/JAHA.
119.012429
6. Kosuge M, Ebina T, Hibi K, Iwahashi N, Tsukahara K, Endo M,
Maejima N, Hashiba K, Suzuki H, Umemura S, et al. High QRS score on
admission strongly predicts impaired myocardial reperfusion in patients with
a first anterior acute myocardial infarction. Circ J. 2011;75:626–632. doi:
10.1253/circj.cj-10-1053
7. Shiomi H, Kosuge M, Morimoto T, Watanabe H, Taniguchi T, Nakatsuma
K, Toyota T, Yamamoto E, Shizuta S, Tada T, et al. QRS score at presen-
tation electrocardiogram is correlated with infarct size and mortality in
ST-segment elevation myocardial infarction patients undergoing primary
percutaneous coronary intervention. Circ J. 2017;81:1129CJ-16-1255–
1129CJ-16-1136. doi: 10.1253/circj.cj-16-1255
8. Armstrong PW, Fu Y, Westerhout CM, Hudson MP, Mahaffey KW, White HD,
Todaro TG, Adams PX, Aylward PEG, Granger CB. Baseline Q-wave sur-
passes time from symptom onset as a prognostic marker in ST-segment
elevation myocardial infarction patients treated with primary percutane-
ous coronary intervention. J Am Coll Cardiol. 2009;53:1503–1509. doi:
10.1016/j.jacc.2009.01.046
9. McDonald MA, Fu Y, Zeymer U, Wagner G, Goodman SG, Ross A,
Granger CB, Werf FV de, Armstrong PW; Investigators A-4 P. Adverse out-
comes in fibrinolytic-based facilitated percutaneous coronary intervention:
insights from the ASSENT-4 PCI electrocardiographic substudy. Eur Heart
J. 2008;29:871–879. doi: 10.1093/eurheartj/ehn078
10. Kusama I, Hibi K, Kosuge M, Nozawa N, Ozaki H, Yano H, Sumita S,
Downloaded from http://ahajournals.org by on November 27, 2022
Tsukahara K, Okuda J, Ebina T, et al. Impact of plaque rupture on infarct
size in ST-segment elevation anterior acute myocardial infarction. J Am Coll
Cardiol. 2007;50:1230–1237. doi: 10.1016/j.jacc.2007.07.004
11. Heusch G, Gersh BJ. The pathophysiology of acute myocardial infarction
and strategies of protection beyond reperfusion: a continual challenge. Eur
Heart J. 2017;38:ehw224. doi: 10.1093/eurheartj/ehw224
12. Ezekowitz JA, Kaul P, Bakal JA, Armstrong PW, Welsh RC, McAlister FA.
Declining in-hospital mortality and increasing heart failure incidence in elderly
patients with first myocardial infarction. J Am Coll Cardiol. 2009;53:13–20.
doi: 10.1016/j.jacc.2008.08.067
13. Gohbara M, Hibi K, Mitsuhashi T, Maejima N, Iwahashi N, Kataoka S,
Akiyama E, Tsukahara K, Kosuge M, Ebina T, et al. Glycemic variability on
continuous glucose monitoring system correlates with non-culprit vessel
coronary plaque vulnerability in patients with first-episode acute coronary
syndrome – optical coherence tomography study. Circ J. 2015;80:202–
210. doi: 10.1253/circj.CJ-15-0790
14. Waha S de, Patel MR, Granger CB, Ohman EM, Maehara A, Eitel I,
Ben-Yehuda O, Jenkins P, Thiele H, Stone GW. Relationship between micro-
vascular obstruction and adverse events following primary percutaneous
coronary intervention for ST-segment elevation myocardial infarction: an
individual patient data pooled analysis from seven randomized trials. Eur
Heart J. 2017;38:3502–3510. doi: 10.1093/eurheartj/ehx414
15. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T,
Seguchi O, Myoishi M, Minamino T, Ohara T, et al. Human atrial natriuretic
peptide and nicorandil as adjuncts to reperfusion treatment for acute myo-
cardial infarction (J-WIND): two randomised trials. Lancet. 2007;370:1483–
1493. doi: 10.1016/S0140-6736(07)61634-1
16. Endo M, Hibi K, Shimizu T, Komura N, Kusama I, Otsuka F, Mitsuhashi T,
Iwahashi N, Okuda J, Tsukahara K, et al. Impact of ultrasound attenuation
and plaque rupture as detected by intravascular ultrasound on the inci-
dence of no-reflow phenomenon after percutaneous coronary interven-
tion in ST-segment elevation myocardial infarction. JACC Cardiovasc Interv.
2010;3:540–549. doi: 10.1016/j.jcin.2010.01.015
Circ Cardiovasc Imaging. 2022;15:e014497. DOI: 10.1161/CIRCIMAGING.122.014497
Impact of Culprit-Lesion Morphology on RPEMI
17. Kubo T, Imanishi T, Takarada S, Kuroi A, Ueno S, Yamano T, Tanimoto T,
Matsuo Y, Masho T, Kitabata H, et al. Assessment of culprit lesion morphol-
ogy in acute myocardial infarction ability of optical coherence tomography
compared with intravascular ultrasound and coronary angioscopy. J Am Coll
Cardiol. 2007;50:933–939. doi: 10.1016/j.jacc.2007.04.082
18. Pu J, Mintz GS, Biro S, Lee J-B, Sum ST, Madden SP, Burke AP, Zhang
P, He B, Goldstein JA, et al. Insights into echo-attenuated plaques, echo-
lucent plaques, and plaques with spotty calcification: novel findings from
comparisons among intravascular ultrasound, near-infrared spectroscopy,
and pathological histology in 2,294 human coronary artery segments. J Am
Coll Cardiol. 2014;63:2220–2233. doi: 10.1016/j.jacc.2014.02.576
19. Nishihira K, Yamashita A, Imamura T, Hatakeyama K, Sato Y, Nakamura H,
Yodoi J, Ogawa H, Kitamura K, Asada Y. Thioredoxin in coronary culprit lesions:
possible relationship to oxidative stress and intraplaque hemorrhage. Athero-
sclerosis. 2008;201:360–367. doi: 10.1016/j.atherosclerosis.2008.03.005
20. Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis
and high-risk plaque part I: evolving concepts. J Am Coll Cardiol. 2005;
46:937–954. doi: 10.1016/j.jacc.2005.03.074
21. Kaikita K, Ogawa H, Yasue H, Takeya M, Takahashi K, Saito T, Hayasaki K,
Horiuchi K, Takizawa A, Kamikubo Y, et al. Tissue factor expression on mac-
rophages in coronary plaques in patients with unstable angina. Arterioscler
Thromb Vasc Biol. 1997;17:2232–2237. doi: 10.1161/01.ATV.17.10.2232
22. Sato Y, Hatakeyama K, Yamashita A, Marutsuka K, Sumiyoshi A, Asada Y.
Proportion of fibrin and platelets differs in thrombi on ruptured and eroded
coronary atherosclerotic plaques in humans. Heart. 2005;91:526. doi:
10.1136/hrt.2004.034058
23. Jia H, Dai J, Hou J, Xing L, Ma L, Liu H, Xu M, Yao Y, Hu S, Yamamoto E,
et al. Effective anti-thrombotic therapy without stenting: intravascular optical
coherence tomography-based management in plaque erosion (the EROSION
study). Eur Heart J. 2017;38:792–800. doi: 10.1093/eurheartj/ehw381
24. Saia F, Komukai K, Capodanno D, Sirbu V, Musumeci G, Boccuzzi G,
Tarantini G, Fineschi M, Tumminello G, Bernelli C, et al. Eroded versus rup-
tured plaques at the culprit site of STEMI in vivo pathophysiological features
and response to primary PCI. JACC Cardiovasc Imaging. 2015;8:566–575.
doi: 10.1016/j.jcmg.2015.01.018
25. Vergallo R, Crea F. Atherosclerotic plaque healing. N Engl J Med.
2020;383:846–857. doi: 10.1056/NEJMra2000317
26. Kramer MCA, Rittersma SZH, Winter RJ de, Ladich ER, Fowler DR,
Liang Y-H, Kutys R, Carter-Monroe N, Kolodgie FD, van der Wal AC, et al.
Relationship of thrombus healing to underlying plaque morphology in sud-
den coronary death. J Am Coll Cardiol. 2010;55:122–132. doi: 10.1016/j.
jacc.2009.09.007
27. Heusch G, Kleinbongard P, Böse D, Levkau B, Haude M, Schulz R,
Erbel R. Coronary microembolization: from bedside to bench and
back to bedside. Circulation. 2009;120:1822–1836. doi: 10.1161/
CIRCULATIONAHA.109.888784
28. Bulluck H, Foin N, Tan JW, Low AF, Sezer M, Hausenloy DJ. Invasive assess-
ment of the coronary microcirculation in reperfused ST-segment–elevation
myocardial infarction patients. Circ Cardiovasc Interv. 2017;10:e004373.
doi: 10.1161/CIRCINTERVENTIONS.116.004373
29. Maria GLD, Patel N, Kassimis G, Banning AP. Spontaneous and proce-
dural plaque embolisation in native coronary arteries: pathophysiology,
diagnosis, and prevention. Scientifica. 2013;2013:364247. doi: 10.1155/
2013/364247
30. Cung T-T, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D,
Bonnefoy-Cudraz E, Guérin P, Elbaz M, Delarche N, et al. Cyclosporine
before PCI in patients with acute myocardial infarction. N Engl J Med.
2015;373:1021–1031. doi: 10.1056/NEJMoa1505489
31. Bulluck H, Sirker A, Loke YK, Garcia-Dorado D, Hausenloy DJ. Clinical benefit
of adenosine as an adjunct to reperfusion in ST-elevation myocardial infarc-
tion patients: an updated meta-analysis of randomized controlled trials. Int J
Cardiol. 2016;202:228–237. doi: 10.1016/j.ijcard.2015.09.005
32. Stone GW, Maehara A, Witzenbichler B, Godlewski J, Parise H, Dambrink
J-HE, Ochala A, Carlton TW, Cristea E, Wolff SD, et al. Intracoronary abciximab
and aspiration thrombectomy in patients with large anterior myocardial infarc-
tion: the INFUSE-AMI randomized trial. JAMA. 2012;307:1817–1826. doi:
10.1001/jama.2012.421
33. Ortiz-Pérez JT, Meyers SN, Lee DC, Kansal P, Klocke FJ, Holly TA, Davidson CJ,
Bonow RO, Wu E. Angiographic estimates of myocardium at risk during acute
myocardial infarction: validation study using cardiac magnetic resonance imag-
ing. Eur Heart J. 2007;28:1750–1758. doi: 10.1093/eurheartj/ehm212
November 2022 823