European Heart Journal (2020) 41, 3549–3560 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehaa703 Acute coronary syndromes

Differential immunological signature at the

culprit site distinguishes acute coronary
syndrome with intact from acute coronary
syndrome with ruptured fibrous cap: results

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from the prospective translational
OPTICO-ACS study
David M. Leistner 1,2,3*,†, Nicolle Kränkel 1,2†, Denitsa Meteva 1,2,
Youssef S. Abdelwahed 1,2,3, Claudio Seppelt1,2, Barbara E. Stähli1,2,
Himanshu Rai 5, Carsten Skurk1,2, Alexander Lauten1,2,
Hans-Christian Mochmann1, Georg Fröhlich1,2, Ursula Rauch-Kröhnert1,2,
Eduardo Flores 1, Matthias Riedel 1,2, Lara Sieronski1,2, Sylvia Kia1,2,
Elisabeth Strässler1,2, Arash Haghikia 1,2,3, Fabian Dirks 1,3,
Julia K. Steiner1,2, Dominik N. Mueller 2,3,6,7, Hans-Dieter Volk 3,8,
Jens Klotsche9, Michael Joner4,5, Peter Libby10, and Ulf Landmesser1,2,3
1
Department of Cardiology, University Heart Centre Berlin and Charité University Medicine Berlin, Campus Benjamin-Franklin (CBF), Hindenburgdamm 30, Berlin D-12203, Germany;
2
DZHK (German Centre for Cardiovascular Research) Partner Site Berlin, Berlin 12203, Germany; 3Berlin Institute of Health (BIH), Berlin 10117, Germany; 4Department of
Cardiology and ISAR Research Centre, German Heart Centre, Munich, 80636, Germany; 5DZHK (German Centre for Cardiovascular Research) Partner Site Munch, Munich,
80636, Germany; 6Experimental and Clinical Research Centre (ECRC), a cooperation of Charité University Medicine Berlin and Max Delbruck Centre for Molecular Medicine in
the Helmholtz Association, Berlin 13125, Germany; 7Max Delbruck Centre for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany; 8Institute for Medical
Immunology and BIH Centre for Regenerative Therapies (BCRT), and Berlin Centre for Advanced Therapies (BeCAT), Charité University Medicine Berlin, Berlin 13353,
Germany; 9German Rheumatism Research Centre Berlin, and Institute for Social Medicine, Epidemiology und Heath Economy, Charité University Medicine Berlin, Campus
Charité Mitte, Berlin 10117, Germany; and 10Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave
Louis Pasteur, Boston, MA 02115, USA

Received 23 January 2020; revised 15 May 2020; editorial decision 6 August 2020; accepted 13 August 2020
Listen to the audio abstract of this contribution

See page 3561 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa721)

Aims Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for
approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS
caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study
programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact
fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping.
...................................................................................................................................................................................................
Methods The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultan-
and results eous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements
across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of
ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The

* Corresponding author. Tel: þ49-30-450-513-702, Fax: þ49-30-450-513-947, Email: david-manuel.leistner@charite.de

†
These authors contributed equally to this work.
C The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
Published on behalf of the European Society of Cardiology. All rights reserved. V
3550 D.M. Leistner et al.

IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely
localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions
demonstrated selective enrichment in both CD4þ and CD8þ T-lymphocytes (þ8.1% and þ11.2%, respectively,
both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV)
were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8þ T-lymphocytes was detect-
able in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-
cell effector molecules granzyme A (þ22.4%), perforin (þ58.8%), and granulysin (þ75.4%) as compared with RFC
plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate cor-
onary flow near a bifurcation, demonstrated an enhanced adhesion of CD8þT cells. Finally, both CD8þT cells and
their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in
IFC-ACS.
...................................................................................................................................................................................................

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Conclusions The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of
the adaptive immune system, particularly CD4þ and CD8þ T-cells and their effector molecules. The different im-
mune signatures identified in this study advance the understanding of coronary plaque progression and may provide
a basis for future development of personalized therapeutic approaches to ACS with IFC.
...................................................................................................................................................................................................
Trial The study was registered at clinicalTrials.gov (NCT03129503).
registration
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Graphical Abstract

.....................................................................................................................................................................................................

Keywords Acute coronary syndrome • Plaque rupture • Optical coherence tomography • CD8þ • T cells • Shear
stress • Endothelial erosion
Differential immunological signature at the ACS culprit site 3551

Translational perspective
The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide the
basis for future development of personalized therapeutic approaches to acute coronary syndromes with intact fibrous cap.

..
Introduction .. Written informed consent was obtained from all participating subjects
.. and the study was registered at ClinicalTrials.gov (NCT03129503).
Acute coronary syndromes (ACS) remain the most devastating clin- ..
..
ical manifestation of coronary artery disease (CAD).1 Autopsy stud- ..
ies indicated that ACS frequently arise from rupture of the coronary .. Optical coherence tomography image
..
fibrous cap (RFC = ruptured fibrous cap), whereby the highly .. acquisition and analysis
..

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thrombogenic necrotic core is exposed to the circulating blood, trig- .. All OCTs were analysed for the underlying ACS-causing culprit patho-
gering thrombus formation, and threatening myocardial perfusion.1–4 .. physiology by two independent core labs and according to the predefined
The interplay between inflammation and coagulation at sites of vul- .. study-specific standard operating procedure using the Medis QIvus 3.0
..
nerable atherosclerotic plaques prone to rupture has undergone ex- .. (Medis Medical Imaging Service, Leiden, The Netherlands; see
tensive investigation and the concept of plaque rupture causing ACS .. Supplementary material online, S1B and C). The rate of absolute agree-
.. ment/inter-observer variability for the diagnosis RFC-ACS was 94.3%
has gained wide acceptance.3,5,6 However, autopsy studies have sug- ..
gested another mechanism of ACS, i.e. coronary plaque erosion,
.. (Π= 0.82) and for IFC-ACS 95.4% (Π= 0.86), and the rate of absolute
.. agreement/intra-observer variability for RFC-ACS 98.5% (Π= 0.96) and
characterized by thrombus formation on a plaque with intact fibrous .. 99.2% (Π= 0.98) for IFC-ACS, respectively. Cases with disagreement on
cap (IFC = intact fibrous cap) and endothelial injury on the luminal
..
.. the type of the ACS-causing culprit lesion were reassessed to reach
surface of the plaque.2,5,7–9 .. agreement with respect to all published data and definitions20
Contemporary intravascular imaging studies implicate IFC in up to
..
.. (Supplementary material online, S1B and C and S2). Cases without con-
one-third of ACS.10–12 The underlying pathophysiological mecha- .. sensus between the two core labs (n = 5; 3.6% of all OCT scans) were
nisms of IFC-ACS remain incompletely understood. As effective lipid
.. excluded from the analysis.
..
lowering and other current interventions alter atherosclerotic plaque ..
..
composition in a manner that may render them less susceptible to ..
rupture, plaque erosion may rise as a mechanism of ACS and import- .. Biosample collection, analysis, flow
..
antly contribute to residual atherothrombotic risk.5,13,14 A better .. cytometry-based immunophenotyping,
understanding of pathophysiological pathways leading to IFC-ACS .. plasma cytokine profiling, thrombus analysis,
..
may provide the basis for personalized treatment strategies in ACS .. and plasma microvesicle quantification
patients, as the recent EROSION trial started to illustrate.15 Optical ..
.. After diagnostic angiography and before PCI, systemic blood samples
coherence tomography (OCT), a high-resolution intravascular imag- .. (SYS) were obtained by aspiration of 30 mL blood from the arterial
ing modality, permits in vivo visualization of the vessel wall and a ..
.. sheath (Take home figure). Coronary thrombi and blood samples were
detailed characterization of the mechanisms of ACS.16,17 The present .. obtained directly from the ACS-causing culprit lesion (LOC) by
study therefore sought to define immunological patterns of IFC- vs. .. aspiration of 30 mL blood using the Export AdvanceTM aspiration cath-
..
RFC-culprit lesions by combining for the first time in vivo culprit .. eter system (Medtronic, Minneapolis, MN, USA, Take home figure). After
plaque analysis by OCT and a detailed analysis of immunological and .. filtering thrombotic components from the LOC samples, flow cytome-
..
biochemical processes directly at the culprit coronary site in a cohort .. try-based immunophenotyping was immediately performed. To deter-
of consecutive ACS patients.
.. mine culprit lesion inflammatory activation, a ‘culprit ratio’ (CR) was
.. calculated by normalizing each individual inflammatory level of the culprit
..
.. lesion (LOC) to those measured systemically at the level of arterial
.. sheath (SYS; Take home figure, Supplementary material online, S1A).
.. Aspirated culprit thrombi underwent immunofluorescence analysis.21,22
..
Methods .. Supplementary material online, S1Aprovides more detailed information.
..
..
Study design and patients ..
The prospective, multicentre OPTICO-ACS (OPTIcal-COherence
.. Analysis of endothelial cell death
..
Tomography in Acute Coronary Syndrome) study was co-ordinated at .. 1  105 flow-sorted CD8þ or CD14þ leucocytes were pre-activated by
the Charité—University Medicine Berlin and the Berlin Institute of Health .. human TransAct (MACS Miltenyl Biotech; Bergisch Gladbach, Germany)
..
(BIH), Germany. A total of 170 patients presenting with ACS [Non-ST .. and added to preconditioned human aortic endothelial cells (HAECs,
segment elevation myocardial infarction (NSTE-ACS)18 or ST segment .. Lonza, Basel, Switzerland) for a duration of 24, 48, and 72 h, before
elevation myocardial infarction (STE-ACS19] undergoing percutaneous
.. cells were harvested and single-cell suspensions were labelled.
..
coronary intervention (PCI) of a clearly determinable culprit lesion in the .. Similarly, the effect of granulysin, perforin, and granzyme A (Enzo Life
absence of active inflammatory or malignant diseases were consecutively .. Sciences, Loerrach, Germany) in different combinations and at a
..
enrolled (Supplementary material online, S1A). Ethical approval was .. concentration of 2 ng/mL—as detected in human plasma samples—
obtained from the local ethics committee (No. EA1/270/16) and the .. on HAEC cell death after 72 h was assessed (for details see
study was conducted in accordance with the Declaration of Helsinki.
.. Supplementary material online, S1A).
3552 D.M. Leistner et al.

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Take home figure In total, 150 patients were included into the prospective translational OPTICO-ACS study (A) and its culprit lesions were
characterized by OCT as well as by local and systematic immunophenotyping: Culprit lesion ratios revealed differential immunological signature with
an enrichment in T-lymphocytes, both CD4þand CD8þ T-cell subpopulations (B) as well as increased T-cell effector molecules at the culprit site dis-
tinguishing acute coronary syndromes with intact fibrous cap from ruptured fibrous cap-acute coronary syndrome. Since acute coronary syndromes
with intact fibrous cap-lesion were often located at bifurcations, endothelial cells were subjected to culture in disturbed laminar flow conditions (C),
i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8þT cells. Finally, both CD8þT cells and their cytotoxic
effector molecules caused endothelial cell death, a key pathophysiological mechanism in acute coronary syndromes with intact fibrous cap.

.. selection operator) method for variable selection. Statistical analyses were

Adhesion to flow-primed endothelium ..
To investigate adhesion to flow-primed endothelium, HAECs were .. performed using STATA 12.1 (StataCorp, TX, USA).
..
grown to confluence in double-y-shaped microchannel slides (Ibidi, ..
Martinsried, Germany) exposed to 12 dyn/cm2 flow for 48 h prior to ..
..
the experiment. Flow-sorted CD8þT cells and CD14þmonocytes
were labelled with DiD and DiO (both Invitrogen, Carlsbad, USA),
respectively, and 1  106 labelled cells were added to the flow reser-
voir for 30 min. After flow-termination, non-adherent cells were
washed out, cells were fixed with 4% paraformaldehyde and the
number of cells adhering in the nine laminar-flowed fields was
assessed by fluorescence phase-contrast microscope (for details see
Supplementary material online, S1A).
Statistical analysis
Details are provided in Supplementary material online, S1A. In brief, median
regression analysis was used to compare the local and peripheral levels as
well as the CR for immune cells and cytokines among the three groups.
Pairwise group comparisons were conducted by a post hoc test after fitting
the median regression model. Multivariable median regression models
were fitted to analyse the association between the CR of T cells and cyto-
kines within the three groups and other clinical variables of interest. Panel
analysis was conducted by using the LASSO (least absolute shrinkage and
.. Results
..
.. Baseline characteristics
..
.. Out of 170 ACS patients undergoing OCT imaging, 130 patients
..
.. were included in the final analysis. Patients were excluded due
.. to suboptimal image quality or massive thrombus burden
..
.. (n = 28), angiographic non-detectable in-stent thrombosis
.. (n = 2), spontaneous coronary artery dissection (n = 2), calcified
..
.. nodules (n = 3), and inconclusive findings on OCT imaging
.. across the two independent OCT core labs (n = 5,
..
.. Supplementary material online, S2). Plaque erosion (IFC-ACS)
.. and plaque rupture (RFC-ACS) were identified in 32 (24.6%)
..
.. and 98 (75.4%) patients, respectively.
.. A total of 87 (66.9%) patients presented with STE-ACS. Table 1
..
.. summarizes the baseline clinical and laboratory data. Patients were
.. predominantly men (n = 103; 79.2%) and mostly (n = 124; 95.4%)
..
.. presented with the first CAD event. The prevalence of cardiovas-
.. cular risk factors was high with hypertension and type 2 diabetes
Differential immunological signature at the ACS culprit site 3553

Table 1 Baseline characteristics of the study population (n 5 130)

RFC-ACS (n 5 98) IFC-ACS (n 5 32) P-value

....................................................................................................................................................................................................................
Patient characteristics
Age, years 64.4 ± 12 63.0 ± 10 0.44
Male, n (%) 76 (78%) 27 (84%) 0.41
Family history for CAD, n (%) 39 (45%) 14 (48%) 0.79
Smoking, n (%) 21 (23%) 7 (25%) 0.50
Diabetes mellitus, n (%) 18 (18%) 7 (22%) 0.66
Arterial hypertension, n (%) 72 (74%) 23 (72%) 0.86
Dyslipidaemia, n (%) 73 (75%) 17 (57%) 0.05

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BMI, mean ± SD 27.2 ± 4 27.5 ± 4 0.69
Previous history of PCI, n (%) 4 (4.1%) 2 (6.3%) 0.61
Laboratory data
Total cholesterol, mg/dL 187 ± 43 172 ± 42 0.15
LDL cholesterol, mg/dL 122 ± 36 112 ± 40 0.25
Serum creatinine, mg/dL 0.9 ± 0.2 1.00 ± 0.2 0.12
Hemoglobin, g/dL 14.5 ± 1.4 14.4 ± 2.0 0.92
Leucocytes, per nL 11.4 ± 3.7 11.2 ± 4.1 0.78
Lymphocytes, per nL 2.9 ± 3.7 2.3 ± 0.7 0.72
hs-CRP, mg/L 5.6 ± 15.4 6.4 ± 20.3 0.80
ACS characteristics
Presentation as STE-ACS, n (%) 64 (65%) 23 (72%) 0.49
CK peak (U/I), mean ± SD 1498 ± 1444 1259 ± 1441 0.42
LV-EF at discharge (%), mean ± SD 56 ± 10 54 ± 11 0.35
TIMI flow, n (%)
0 52 (72%) 12 (71%) 0.66
1 8 (11%) 3 (18%)
2 10 (14%) 1 (6%)
3 2 (3%) 1 (6%)
Culprit Segment TIMI flow <1, n (%) 42 (43%) 11 (34%) 0.40
Culprit vessel, n (%)
LM 0 (0%) 0 (0%) 0.69
LAD 48 (49%) 18 (56%)
LCX 14 (14%) 3 (9%)
RCA 36 (37%) 11 (34%)
Involved culprit segment, n (%)
Proximal 40 (41%) 14 (44%) 0.77
Middle 44 (45%) 15 (47%)
Distal 14 (14%) 3 (9%)
Number of diseased vessels, n (%)
1 46 (47%) 18 (56%) 0.45
2 33 (34%) 7 (22%)
3 19 (19%) 7 (22%)
Medical therapy before admission
Aspirin 250 mg, n (%) 96 (98%) 31 (97%) 0.41
(LMW-)Heparin, n (%) 97 (99%) 30 (94%) 0.09
Antiplatelet therapy, n (%) 15 (15%) 2 (7%) 0.18
(Loading dose Clopidogrel/Prasugrel/Ticagrelor)
PCI characteristics
Total stented length (mm) 34.0 ± 16.4 29.6 ± 15.2 0.18
Largest stent diameter (mm) 3.3 ± 0.5 3.2 ± 0.5 0.38

BMI, body mass index; CK, creatinine kinase; CRP, C-reactive protein; HCT, hematocrit; IFC-ACS, intact fibrous cap-acute coronary syndrome; LAD, left anterior descending
artery; LCX, left circumflex artery; LDL, low-density lipoprotein; LM, left main; LMW, low-molecular-weight; LVEF, left ventricular ejection fraction; n, number; PCI, percutan-
eous coronary intervention; RCA, right coronary artery; RFC-ACS, ruptured fibrous cap-acute coronary syndrome; SD, standard deviation; STE-ACS, ST-elevation myocardial
infarction; TIMI, thrombolysis in myocardial Infarction.
3554 D.M. Leistner et al.

Table 2 Optical coherence tomography characteristics of the ACS-causing culprit lesion within the study cohort
(n 5 130)

RFC-ACS (n 5 98) IFC-ACS (n 5 32) P-value

....................................................................................................................................................................................................................
OCT-culprit lesion characteristics
MLA (mm2), mean ± SD 1.82 ± 0.6 1.78 ± 0.8 0.74
Thrombus characteristics
CL-associated thrombus formation, n (%) 97 (100%) 32 (100%) 1.0
Thrombus score, mean ± SD 126 ± 87 85 ± 74 0.02
Thrombus type, n (%)
Red 2 (2%) 0 (0%) < 0.001

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White 26 (27%) 22 (69%)
Mixed 70 (71%) 10 (31%)
Culprit plaque characteristics
Fibroatheroma, n (%) 97 (99%) 29 (94%) 0.08
Lipid-rich plaque, n (%) 98 (100%) 29 (91%) 0.01
Thin-attenuated plaque, n (%) 96 (98%) 16 (50%) <0.001
Mean FC thickness (mm), mean ± SD 55.1 ± 7 80.1 ± 55 <0.001
Lipid index, mean ± SD 3080.8 ± 1318.9 2007.0 ± 1377.8 <0.001
Calcification
Mean calcium arc, mean ± SD) 48 ± 39 32 ± 33 0.04
Mean calcified length, mean ± SD 3.85 ± 4.3 1.08 ± 6.6 0.01
Relation to bifurcation
Distance to nearest branch, mean ± SD 6.27 ± 4.6 3.92 ± 3.9 0.01
Branch within 3 mm, n (%) 29 (29.6%) 19 (61.3%) 0.01
Details of culprit lesions within/near bifurcations
Bifurcation: LAD/Diagonal branch, n (%) 15 (51.7%) 11 (57.9%) 0.47
Bifurcation: LCX/Marginal-branch, n (%) 5 (17.2%) 1 (5.3%)
Bifurcation: Other location, n (%) 9 (31.1%) 7 (36.8%)
Bifurcation: Medina 1-1-0, n (%) 6 (20.7%) 1 (5.3%) 0.14
Bifurcation: Medina 1-1-1, n (%) 6 (20.7%) 2 (10.5%) 0.36
Bifurcation: Medina 0-1-0/1-0-0, n (%) 12 (51.7%) 9 (47.4%) 0.77
Bifurcation: Medina 0-0-1, n (%) 5 (17.2%) 7 (36.8%) 0.13

FC, fibrous cap; IFC-ACS, intact fibrous cap-acute coronary syndrome; MLA, minimum lumen area; n, number; RFC-ACS, ruptured fibrous cap-acute coronary syndrome; SD,
standard deviation; TCFA, thin-cap fibroatheroma.

observed in 95 (73.1%) and 25 (19.2%) patients, respectively. The .. 98%; P < 0.01). The IFC-ACS lesions were more frequently located
..
occurrence of cardiovascular risk factors, the type of index ACS .. near coronary bifurcations (61.3% vs. 29.6%; P = 0.01), yielding a
events, the localization of the culprit lesion, TIMI flow rate, labora-
.. shorter lesion-to-bifurcation distance (3.9 ± 3.9 mm vs.
..
tory data including systemic inflammatory markers and maximum .. 6.3 ± 4.6 mm; P = 0.01, Table 2).
creatinine kinase (CK) levels, as well as left ventricular systolic
..
..
function did not differ among patients with RFC-ACS and IFC- .. Concentration of T-lymphocytes and
ACS, except for dyslipidaemia (75% vs. 57%; P = 0.05),
..
.. related cytokines
respectively. ..
.. A higher CR of T-lymphocytes (P = 0.02) was observed in patients
.. with plaque erosions (IFC-ACS), including both CD4þ T-cells
..
Optical coherence tomography findings .. (1.05 vs. 0.98; P = 0.02) and CD8þ T-cells (1.11 vs. 1.00; P = 0.01,
Lumen reduction as assessed by minimum lumen area23 did not dif- .. Table 3; Supplementary material online, S3). The observed rela-
..
fer between RFC-ACS and IFC-ACS (1.82 ± 0.6 mm2 vs. 1.78 ± 0.8 .. tions remained significant after adjusting for systemic inflammatory
mm2, P = 0.74, Table 2). Compared with RFC-ACS, IFC-ACS culprit .. markers, TIMI flow grade, and type of culprit vessel
..
plaques were less often lipid-rich (91% vs. 100%; P = 0.01), had less .. (Supplementary material online, S4). Neutrophils, granulocytes,
calcification (mean calcium arc 32 ± 33 vs. 48 ± 39 ; P = 0.01), and
.. and natural killer cells only showed trends towards lower levels in
..
overlying thrombus (thrombus score23 85 ± 74 vs. 126 ± 87; .. patients with RFC-ACS (Table 3 and Supplementary material on-
P = 0.02), and fewer were thin-cap fibroatheroma (TCFA: 50% vs.
.. line, S3). In multivariable linear regression analysis, both plaque
Differential immunological signature at the ACS culprit site 3555

Table 3 Culprit ratio of different immune cells

RFC-ACS (n 5 98) IFC-ACS (n 5 32) P-value % IFC-ACS vs. RFC-ACS

....................................................................................................................................................................................................................
Innate immunity
Monocytes 0.99 (0.9) 1.02 (0.9) 0.19 103.6
Granulocytes 0.99 (0.9) 0.96 (0.9) 0.32 96.6
Neutrophils 0.99 (0.9) 0.97 (0.9) 0.44 98.0
NK cells 1.00 (0.7) 1.00 (0.9) 0.24 99.5
Adaptive immunity
B cells 0.96 (0.8) 1.03 (0.9) 0.07 106.9
T cells 0.98 (0.9) 1.07 (1.0) 0.02 109.2

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CD8þ T cells 1.00 (0.8) 1.11 (1.0) 0.01 111.2
CD4þ T cells 0.98 (0.9) 1.05 (1.0) 0.02 108.1

All values are expressed as median (25th percentile); % change based on median.
IFC-ACS, intact fibrous cap-acute coronary syndrome; NK cells, natural killer cells; RFC-ACS, ruptured fibrous cap-acute coronary syndrome; SD, standard deviation.

Table 4 Multivariate regression analysis of different factors influencing culprit ratio of CD81T-cells

Unstandardized estimates Standardized estimates

........................................................... ......................................................
Beta 95% CI Beta 95% CI P-value
....................................................................................................................................................................................................................
RFC-ACS vs. IFC-ACS 0.26 0.13; 0.39 0.26 0.06; 0.53 <0.001
MLA, mm2 -0.03 -0.10; 0.05 -0.10 -0.33; 0.13 0.45
Thrombus score 0.26 -0.22; 0.73 0.27 -0.02; 0.52 0.29
Mean fibrous cap -0.002 -0.004; -0.001 -0.18 -0.42; -0.05 0.01
thickness, mm
Presence of TCFA 0.001 -0.008; 0.009 0.02 -0.22; 0.25 0.92
Age, years 0.001 -0.003; 0.005 0.11 -0.12; 0.33 0.61
Time from beginning -0.001 -0.002; 0.001 -0.07 -0.31; 0.17 0.68
of symptoms to PCI,
min
LVEF, % -0.002 -0.036; 0.032 -0.03 -0.26; 0.21 0.92
Leucocytes, nL 0.006 -0.008; 0.020 0.19 -0.06; 0.44 0.37
hs-CRP, mg/L -0.001 -0.003; 0.004 -0.06 -0.31; 0.20 0.84
CK Max, U/L -0.001 -0.001; 0.001 -0.07 -0.32; 0.17 0.79
Distance to nearest 0.001 -0.015; 0.016 0.04 -0.31; 0.38 0.93
site-branch, mm
Site-branch within -0.02 -0.16; 0.12 -0.12 -0.44; 0.20 0.79
3 mm to CL

CI, confidence interval; CK, creatinine kinase; CL, culprit lesion; hs-CRP, high-sensitive C-reactive protein; IFC-ACS, intact fibrous cap-acute coronary syndrome; LVEF, left ven-
tricular ejection fraction; MLA, minimum lumen area; n, number; RFC-ACS, ruptured fibrous cap-acute coronary syndrome; TCFA, thin-cap fibroatheroma.

..
erosion (b = 0.256; P < 0.01) and thicker fibrous caps (b = -0.002; .. Investigating a panel of cytokines reflecting different immuno-
P = 0.01) emerged as independent predictors of an increased cor- .. modulatory pathways (Supplementary material online, S6) pla-
..
onary-to-peripheral CD8þ T-lymphocyte ratio (Figure 1 and Table .. que rupture was associated with an increased culprit lesion
4). Thrombotic material harvested at sites of IFC-ACS displayed a .. gradient of IL-8 (P = 0.01), TNF-a (P = 0.02), MIP-1ß (P < 0.01)
..
higher percentage of CD8þ T-lymphocytes than that from sites of .. (Figure 2), while IFC-ACS displayed higher ratios for cytotoxic
RFC-ACS (Supplementary material online, S5A). Patients with pla- .. effector molecules, including granzyme A (P = 0.02), granulysin
..
que erosion (IFC-ACS) had a higher coronary-to-peripheral ratio .. (P = 0.01), and perforin (P = 0.04) (Figure 2). Differences among
of T-lymphocyte-associated extracellular circulating MV and .. groups remained significant after adjustment for systemic inflam-
..
CD8þ T-lymphocytes-associated MV; Supplementary material .. matory markers including hs-CRP and leucocytes and TIMI flow
online, S5B). .. grade (Supplementary material online, S4).
.
3556 D.M. Leistner et al.

MIP-1β(CR)
RFC-ACS (Reference)
Interleukin-6 (CR)

T-cell effector
molecules
Granulysin (CR)
IFC-ACS
Perforin (CR)
Granzyme A (CR)
T cells (CR)
CD4+T cells (CR)
CD8+T cells (CR)
CL: Calcium superficial
Distance CL to bifurcation
parameters

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CL: Culprit plaque TCFA
OCT-

CL: Mean thickness culprit plaque cap

CL: Lipid Index
CL: Thrombus Score

-2 -1.5 -1 -0.5 0 0.5 1 1.5 2

Standardized difference (%) between IFC-ACS as compared to RFC-ACS
Abbreviations: RFC-ACS means rupture fibrous cap acute coronary syndrome;
IFC-ACS = intact fibrous cap-acute coronary syndrome; FC = fibrous cap; (reference)
TCFA= thin cap fibroatheroma; CL= culprit lesion; CR= culprit ratio.

Figure 1 Hierarchical clustering of Pearson’s correlations including parameters of immunophenotyping and OCT-parameters reveals significant
differences among patients with acute coronary syndromes with intact fibrous cap (blue lines depicting standard differences) and ruptured fibrous
cap-acute coronary syndrome (reference: red line).

Figure 2 Box plots depicting significant differences in culprit ratio of effector molecules of the innate immune response (Interleukin-8; MIP-1ß,
TNF-alpha) and effector molecules involved in the adaptive immune response (Granzyme A; Granulysin, Perforin) between ruptured fibrous cap-
acute coronary syndrome and acute coronary syndromes with intact fibrous cap.
Differential immunological signature at the ACS culprit site 3557

..
Distinct patterns of acute coronary .. Second, the microenvironment of IFC-ACS lesions demonstrated a
.. particular enrichment in CD4þ T-lymphocytes, CD8þ T-lympho-
syndromes with intact fibrous cap vs. ..
ruptured fibrous cap-acute coronary .. cytes, and T-cell-associated MV and effector molecules. Consistently,
.. a significant higher amount of CD8þ T-lymphocytes was detectable
syndrome ..
.. in thrombi aspirated from IFC-ACS culprit sites. Furthermore, endo-
To discern a distinct clinical pattern for both IFC-ACS and RFC-ACS, .. thelial cells subjected to culture in disturbed laminar flow conditions
hierarchical clustering was performed including clinical characteris- ..
.. demonstrated an enhanced adhesion of CD8þ T-lymphocytes.
tics, OCT data and immunological findings. Based on hierarchical .. Hence, this study emphasizes a novel mechanism in the pathogen-
clustering, patients with IFC-ACS localized closer to bifurcations, had
..
.. esis of IFC-ACS, favouring participation of the adaptive immune sys-
fewer features of advanced atherosclerotic plaques, lower thrombus .. tem that can promote endothelial cell death (Take home figure). CD8þ
burden, increased CD4þ and CD8þ T-lymphocyte and Granzyme A,
..
.. T-lymphocytes congregated particularly near IFC-ACS lesions, which
granulysin, and perforin CR (Figure 1 and Supplementary material on- .. typically localized near coronary bifurcations, sites of disturbed flow,
..

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line, S6). .. and low endothelial shear stress that can also promote atherosclerot-
.. ic plaque formation.24–27 Enhanced integrin-dependent endothelial ad-
..
CD8þ T-lymphocytes and associated .. hesion of CD8þT-lymphocytes occurred in vitro under conditions of
cytokine promote endothelial cell death .. disturbed laminar flow, emphasizing the importance of wall shear
..
in vitro .. stress in the progression of atherosclerotic plaque formation.28
..
In ex vivo co-culture experiments, we explored whether CD8þ T- .. Together these data indicate a novel plausible immunologically
lymphocytes or their effector molecules granulysin, granzyme A, and .. driven pathophysiological mechanism for ACS caused by culprit pla-
.. ques with intact fibrous cap (IFC-ACS), accountable for about one-
perforin mediate endothelial cell injury, known to be principally ..
involved in the development of plaque erosion. The rate of HAECs .. third of ACS cases.10,11,16
..
positive for the DNA dye Sytox Orange, an indication of compro- ..
mised cell membrane integrity, significantly increased in co-culture .. Anatomical characteristics of acute
..
with CD8þ T-lymphocytes as compared with monocytes from the .. coronary syndromes with intact fibrous
same donor (P < 0.05, Supplementary material online, S7A). In line
..
.. cap
with this, stimulation of HAECs with a combination of granulysin, .. The OPTICO-ACS study allowed simultaneous characterization of
granzyme A, and perforin in the concentration range measured in
..
.. IFC-ACS as compared with RFC-ACS at both the morphological and
plasma samples increased endothelial cell death, while each molecule .. inflammatory level. In this study of consecutive cases, plaque erosion
alone did not exert any effect (P < 0.01, Supplementary material on-
..
.. (IFC-ACS) caused ACS in about one-fourth of patients. The lower
line, S7B and S8). .. prevalence of IFC-ACS observed in OPTICO-ACS than in other re-
..
.. cent series may be due to the stringent use of established OCT diag-
In vitro adhesion of CD8þ T-lymphocytes ..
.. nostic criteria and external validation by a second OCT core lab.
in a model of coronary shear stress .. Indeed, most ACS-studies diagnosed IFC-ACS by exclusion.11,29 In
The adhesion patterns of CD8þ T-lymphocytes on flow-precondi-
..
.. contrast to other studies such as EROSION and post-mortem inves-
tioned endothelium were determined in a flow chamber, mimicking .. tigations,11,30,31 the baseline clinical risk and type of ACS event at
the hydrodynamic conditions at sites of coronary bifurcations and
..
.. presentation did not differ between the two types of culprit lesions,
curvatures (Supplementary material online, S9 and S10). The per- .. besides an increased prevalence of dyslipidaemia in RFC-ACS
centage of adherent CD8þ T-lymphocytes, but not monocytes,
..
.. patients.7 The lack of statistically significant differences between clin-
increased significantly (P < 0.01) under conditions of disturbed as .. ical characteristics of patients with IFC- and RFC-ACS may be due to
..
compared with ordinary laminar flow (Supplementary material on- .. the study design, which aimed at a detailed morphological and im-
line, S10A–C). Incubation with anti-integrin-b2 or an anti-integrin-a4 .. munological characterization of IFC-ACS rather than being adequate-
..
blocking antibody reversed this effect (Supplementary material on- .. ly powered to detect differences in clinical characteristics.
line, S11B and C), highlighting the direct interaction between flow- .. The lesions that provoked IFC-ACS had a lower lipid content and
..
conditioned endothelium and homing of T-lymphocytes. This effect .. less superficial calcium than those that caused RFC-ACS. In accordance
was not seen under laminar flow conditions or when monocyte ad- .. with current concepts,32 TCFA predominated in RFC-ACS, but not
..
hesion was investigated (Supplementary material online, S11). .. IFC-ACS. The lower prevalence of TCFA in IFC-ACS, along with33 the
.. predominance of IFC-ACS lesions near coronary bifurcations6,11 sup-
..
.. port the hypothesis that these two substrates for coronary artery
Discussion .. thrombosis involve distinct pathophysiological mechanisms and impli-
..
.. cate the local haemodynamic environment as a determinant.
The prospective, translational OPTICO-ACS study represents an ..
integrated immune and high-resolution intracoronary imaging charac- ..
.. Distinct immunological characteristics of
terization of distinct ACS entities in a large cohort of ACS patients ..
(Take home figure). In particular, this study demonstrated that IFC .. intact fibrous cap vs. ruptured fibrous
..
caused 24.6% and RFC-ACS 75.4% of ACS events, with IFC-CL being .. cap-acute coronary syndrome
characterized by lower lipid content, less calcification, a thicker over-
.. The OPTICO-ACS study tested the hypothesis that IFC-ACS and
..
lying fibrous cap, and a co-localization with bifurcation lesions. . RFC-ACS involve distinct immunological mechanisms. Our novel
3558
results identify a specific immunological signature, characterized by
.. dependent mechanisms could mediate transmigration of T-lympho-
..
accumulation of T-lymphocytes, especially CD8þ T-lymphocytes and
related effector molecules at sites of IFC-ACS.34,35 This finding
remained significant after adjustment for potential confounders and
received support from analyses of thrombus material retrieved from
the culprit artery. The in vitro results demonstrated that CD8þ T-lym-
phocytes and T-cell-related cytotoxic effector molecules, such as
granulysin, perforin, and granzyme A can contribute directly to endo-
thelial cell death. These findings agree with prior experimental and
post-mortem studies, which identified distinct inflammatory proc-
esses in IFC-ACS lesions.32 Quillard et al.36 demonstrated neutrophil
accumulation after endothelial cell denudation in areas of superficial
plaques as well as Toll-like receptor-2 (TLR-2)-dependent endothe-
lial cell death. Those findings highlighted the role of leucocyte-endo-
thelial cell interactions during plaque progression in IFC-ACS,
particularly the polymorphonuclear granulocyte, an innate immune
effector cell.2,7,8,36,37
The novel findings presented here implicate that the adaptive im-
mune system, notably CD8þ T-lymphocytes, may operate in tandem
with innate immune pathways in IFC-ACS. Earlier autopsy studies
concluded that IFC-ACS did not involve inflammation, focused most-
ly on macrophages.3 However, our recent findings suggest a role for
CD8þT-cells in IFC-ACS, immune pathways distinct from macro-
phages, a cell type with established functions in RFC-ACS.5,38 There
are rather few previous studies that investigated potential immuno-
logical differences between RFC-ACS and IFC-ACS, which were
mainly focused on cytokine levels, had a limited sample size and
measured largely systemic levels.29,39–41
As demonstrated in OPTICO-ACS as well as other studies,29 local
immunological alterations do not necessarily correspond with differ-
ences in cytokine concentrations measured in the systemic circula-
tion. Future studies are needed to explore intracellular mechanisms
induced by T-cell effector molecules in the setting of ACS.
Endothelial flow alterations and acute
coronary syndromes with intact fibrous
cap
Chronic hydrodynamic disturbances experienced by the endothe-
lium can modulate adhesion molecule expression, plaque formation,
progression, and destabilization.28,42,43 Plaque size, composition and
geometric changes, along with adverse vessel remodelling alter both
endothelial shear stress, thus impinging upon the plaque itself44 and
influencing the biomechanical plaque stability.45 The proximity of
IFC-ACS lesions to coronary bifurcations—also—provides further
evidence linking shear stress alterations to the occurrence of IFC-
ACS,24–27,42,46,47 a concept further supported by enhanced adhesion
of CD8þ T-lymphocytes in response to disturbed laminar flow
shown by the present in vitro experiments. Although the role of
CD8þ T-lymphocytes in the pathogenesis of atherosclerotic plaque
formation has undergone extensive investigation,48,49 few studies
have examined the impact of differential flow conditions on the en-
hancement of inflammation and plaque activation resulting in ACS.
Animal and histopathologic studies interrogating the innate immune
system implicated a TLR-2-dependent mechanism regulated by shear
stress in the pathophysiology of IFC-ACS.5,50–52 Shear stress-
D.M. Leistner et al.
.. cytes.53 Its contributions, however, have not received enough atten-
.. tion in the context of different culprit lesion morphologies yet. This
..
.. study suggests that shear stress-depended accumulation and activa-
.. tion of CD8þ T-lymphocytes and subsequent T-lymphocyte-medi-
..
.. ated endothelial cell damage may participate pivotally in the
.. pathogenesis of IFC-ACS in humans. As IFC-ACS lesions do not only
..
.. occur near coronary bifurcations, mechanisms in addition to flow
..
... alterations may influence IFC-ACS events. Of note, a recent study
.. has reported an increased gene expression of hyaluronidase 2 in
.. mononuclear cells from patients with IFC-ACS54 and a potential role
..
.. of hyaluronan for T-cell biology.55
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..
..
.. Limitations of the study
..
.. Despite predefined criteria excluding patients with active inflammatory,
.. autoimmune, or malignant disease, as well as patients under anti-inflam-
..
.. matory therapy, we cannot rule out that patients with inapparent co-
.. morbidities may have influenced the results. Second, as thrombus aspir-
..
.. ation was performed in the culprit vessel, the aspirated material may
.. not represent exclusively the culprit lesion microenvironment.
..
.. Furthermore, pre-dilatation, needed to restore coronary blood flow in
.. some patients, may have affected the integrity of the culprit plaque as
..
.. well as the local inflammatory microenvironment. Third, since OCT
.. imaging was not possible in left main disease, coronary bypass graft
..
.. disease, at distal locations, or when identification of the culprit le-
.. sion was unclear, the findings of this study may not extend to
..
.. these patient populations. Fourth, as the definition of IFC-ACS
.. and RFC-ACS required agreement between two independent
..
.. OCT core labs, the exclusion of unclear cases may have intro-
..
.. duced selection bias, and patients with particularly high thrombus
.. burden may have thus not entered this study. Finally, this study
..
.. presents CR as an intra-individual normalization of the local cul-
.. prit microenvironment for systemic inflammatory effects, thereby
..
.. accounting for the heterogeneity of immune responses in the
.. study population and minimizing potential systemic confounding.
..
.. Other methods of normalization, e.g. the aspiration within a non-
.. culprit coronary milieu, may also represent valuable options to
..
.. minimize bias, but may be difficult to ensure in the setting of ACS.
..
..
..
..
.. Conclusions
..
.. The OPTICO-ACS study provides novel evidence for a principal role of
..
.. the adaptive immune system, particularly CD8þ T-lymphocytes and
.. their cytotoxic effector molecules, in the pathogenesis of IFC-ACS,
..
.. which accounts for approximately one-third of ACS. This investigation
.. revealed distinct immunological patterns in IFC-ACS as compared with
..
.. RFC-ACS patients, by characterizing the microenvironment of the cul-
.. prit lesion. The different immune signatures identified in this study ad-
..
.. vance our understanding of coronary plaque progression and provide
.. the basis for future personalized therapeutic approaches to ACS.
..
..
..
..
.. Supplementary material
..
..
. Supplementary material is available at European Heart Journal online.
Differential immunological signature at the ACS culprit site 3559

Acknowledgements .. in patients with ST-segment elevation myocardial infarction: a clinical, angio-

.. graphical, and intravascular optical coherence tomography study. Eur Heart J
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..
catheterization laboratories at Charité University Medicine Berlin. .. 12. Kajander OA, Pinilla-Echeverri N, Jolly SS, Bhindi R, Huhtala H, Niemela K, Fung
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.. erosclerotic plaques. Curr Opin Lipidol 2017;28:434–441.
support as well as the staff of the Berlin Institute of Health (BIH) es- .. 14. Libby P, Pasterkamp G. Requiem for the ‘vulnerable plaque’. Eur Heart J 2015;36:
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Funding .. (the EROSION study). Eur Heart J 2017;38:792–800.
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.. Vergallo R, Hu S, Tian J, Lee H, Park SJ, Jang YS, Raffel OC, Mizuno K, Uemura
Health (BIH) and the German Centre for Cardiovascular Research ..
(DZHK; FKZ: 81Z2100202). Furthermore an educational grant from .. S, Itoh T, Kakuta T, Choi SY, Dauerman HL, Prasad A, Toma C, McNulty I,

Abbott Vascular (formerly: St. Jude Medical) provided OCT imaging. N.K.
.. Zhang S, Yu B, Fuster V, Narula J, Virmani R, Jang IK. In vivo diagnosis of pla-
.. que erosion and calcified nodule in patients with acute coronary syndrome
was supported by the Deutsche Stiftung für Herzforschung (Project: F/ .. by intravascular optical coherence tomography. J Am Coll Cardiol 2013;62:
39/17); P.L. received funding support from the National Heart, Lung, and .. 1748–1758.
.. 17. Higuma T, Soeda T, Abe N, Yamada M, Yokoyama H, Shibutani S, Vergallo
Blood Institute (1R01HL134892), the American Heart Association .. R, Minami Y, Ong DS, Lee H, Okumura K, Jang IK. A combined optical co-
(18CSA34080399), and the RRM Charitable Fund. ..
.. herence tomography and intravascular ultrasound study on plaque rupture,

Conflict of interest: PL is an unpaid consultant to, or involved in clinical

.. plaque erosion, and calcified nodule in patients with st-segment elevation
.. myocardial infarction: incidence, morphologic characteristics, and outcomes
trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, .. after percutaneous coronary intervention. JACC Cardiovasc Interv 2015;8:
Esperion, Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, .. 1166–1176.
.. 18. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger
Medimmune, Merck, Norvo Nordisk, Merck, Novartis, Pfizer, Sanofi- .. MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P,
Regeneron. PL is also a member of scientific advisory board for Amgen, .. Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Group E. 2015
Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals,
..
.. ESC Guidelines for the management of acute coronary syndromes in patients
Olatec Therapeutics, Medimmune, Novartis, XBiotech, Inc. PL laboratory .. presenting without persistent ST-segment elevation: task Force for the
has received research funding in the last 2 years from Novartis. PL is on the .. Management of Acute Coronary Syndromes in Patients Presenting without
.. Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
Board of Directors of XBiotech, Inc. PL has a financial interest in Xbiotech, .. Eur Heart J 2016;37:267–315.
a company developing therapeutic human antibodies. PL interests were .. 19. Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, Borger MA, Di
reviewed and are managed by Brigham and Women’s Hospital and
.. Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi
..
Partners HealthCare in accordance with their conflict of interest policies. .. P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW,
.. Valgimigli M, van ’t Hof A, Widimsky P, Zahger D, Task Force on the manage-
.. ment of ST-segment elevation acute myocardial infarction of the European
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