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CAD and AMI: Research Article
Cardiology
The Interplay between Features of
Plaque Vulnerability and Hemodynamic
Relevance of Coronary Artery Stenoses
Murat Sezer
a Emre Aslanger
b Ozan Cakir
c Adem Atici
a Irem Sezer
d
Alp Ozcan
a Berrin Umman
a Zehra Bugra
a Sabahattin Umman
a
a Department of Cardiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; b Department of
Cardiology, Yeditepe University, Istanbul, Turkey; c Department of Cardiology, Faculty of Medicine, Bulent Ecevit
University, Zonguldak, Turkey; d Department of Cardiology, School of Medicine, Acibadem University, Istanbul,
Turkey
Received: December 26, 2019
Accepted: May 23, 2020
Published online: August 26, 2020
Prof. Murat Sezer
Department of Cardiology, Istanbul Faculty of Medicine
Istanbul University
TR–34093 Istanbul (Turkey)
sezermr @ gmail.com
© 2020 S. Karger AG, Basel
karger@karger.com
www.karger.com/crd
DOI: 10.1159/000508885
Keywords
Atherosclerosis · Coronary artery disease · Coronary
remodeling · Fractional flow reserve · Imaging ·
Interventional cardiology · Intravascular ultrasound ·
Necrotic core · Plaque characteristic
Abstract
Fractional flow reserve (FFR) may not be immune from he-
modynamic perturbations caused by both vessel and lesion
related factors. The aim of this study was to investigate the
impact of plaque- and vessel wall-related features of vulner-
ability on the hemodynamic effect of intermediate coronary
stenoses. Methods and Results: In this cross-sectional study,
patients referred to catheterization laboratory for clinically
indicated coronary angiography were prospectively
screened for angiographically intermediate stenosis (50–
80%). Seventy lesions from 60 patients were evaluated.
Mean angiographic stenosis was 62.1 ± 16.3%. After having
performed FFR assessment, intravascular ultrasound (IVUS)
was performed over the FFR wire. Virtual histology IVUS was
used to identify the plaque components and thin cap fibro-
atheroma (TCFA). TCFA was significantly more frequent (65
vs. 38%, p = 0.026), and necrotic core volume (26.15 ± 14.22
vs. 16.21 ± 8.93 mm3, p = 0.04) was significantly larger in the
positively remodeled than non-remodeled vessels. Remod-
eling index correlated with necrotic core volume (r = 0.396,
p = 0.001) and with FFR (r = –0. 419, p = 0.001). With respect
to plaque components, only necrotic core area (r = –0.262, p
= 0.038) and necrotic core volume (r = –0.272, p = 0.024) were
independently associated with FFR. In the multivariable
model, presence of TCFA was independently associated with
significantly lower mean FFR value as compared to absence
of TCFA (adjusted, 0.71 vs. 0.78, p = 0.034). Conclusion: The
current study demonstrated that for a given stenosis geom-
etry, features of plaque vulnerability such as necrotic core
volume, TCFA, and positive remodeling may influence the
hemodynamic relevance of intermediate coronary stenoses.
© 2020 S. Karger AG, Basel
Introduction
Scrutinizing the ischemic potential of a given coro-
nary stenosis has a pivotal role in revascularization deci-
sion process. In this regard, fractional flow reserve (FFR)
is widely accepted as an indispensable tool in evaluation
Part of this article was presented as an oral contribution at Trans
Catheter Therapeutics (TCT) conference in 2016 and published as
an abstract form in the Journal of the American College of Cardiology
(DOI: 10.1016/j.jacc.2016.09.360).
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DOI: 10.1159/000508885
of hemodynamic significance of an individual stenosis.
However, the hemodynamic effect of a given coronary
stenosis, as assessed by FFR, is influenced by vessel (ves-
sel wall compliance [1, 2], remodeling [3], bending, tor-
tuosity), lesion (minimal luminal area [MLA], lesion ec-
centricity and shape [4], surface properties [5–7], lesion
length [8], and plaque composition [9]), and microcir-
culation (microvascular status [10], myocardial supply
area [11])-related factors. Some of these factors are con-
siderably dynamic and may be influenced by many
pathophysiological processes including inflammation,
plaque vulnerability and evolution, [12] and vascular re-
activity [13]. In particular, it has been observed that 1 in
6–7 lesions with less than 50% angiographic diameter
stenosis had an FFR value that is less than the ischemic
threshold [6, 14], which underscores the importance of
identification of the factors that might contribute to
myocardial ischemia beyond anatomical stenosis sever-
ity. In this regard, coronary plaque and vessel wall-relat-
ed features of vulnerability such as large necrotic core
volume (NCV), presence of thin cap fibroatheroma
(TCFA) and positive vessel remodeling, which are
known to be associated with acute coronary syndromes
and death [15–17], may influence hemodynamic out-
come of those lesions without angiographic significance
[18–21]. Therefore, plaque morphology can be pro-
posed as the missing link between anatomical severity of
the stenosis and its physiological and clinical conse-
quences. In particular, beyond stenosis severity, the im-
pact of features of plaque vulnerability on the net phys-
iological effect of coronary stenoses classified in the up-
per end of the intermediate stenosis spectrum, where the
decision-making process can be expected to be more
critical and in turn, more heavily affect patients’ prog-
nosis, has not been readily clarified yet. Therefore, un-
raveling these potential influences on epicardial resis-
tance may contribute significantly to our understanding
of the interplay between the anatomical substrate and its
physiological and clinical consequences.
In this study, we hypothesized that virtual histology and
gray scale intravascular ultrasound (IVUS)-defined plaque
vulnerability characteristics may influence the hemody-
namic effect of coronary stenoses that are in the upper end
of the angiographically intermediate stenosis spectrum
where scrutinizing the ischemic potential of an angiograph-
ic lesion raises more concern in actual clinical practice.
Therefore, the aim of this study is to elucidate the potential
impact of features of plaque vulnerability on the hemody-
namic relevance of coronary stenoses that can be classified
in the upper end of the intermediate stenosis spectrum.
Methods
Patient Population
Patients referred to catheterization laboratory for clinically in-
dicated coronary angiography were prospectively screened for an-
giographically intermediate stenosis (50–80%) between May 2014
and April 2016. Patients with either stable angina pectoris or non-
ST elevation acute coronary syndrome (NSTEACS) were consecu-
tively included. Physiological significance was evaluated 36–48 h
after acute event in patients presented with NSTEACS. Patients
with previous coronary artery bypass surgery and severe valvular
disease were excluded from the study.
Study Protocol
Intracoronary Hemodynamic Measurements
For the assessment of the hemodynamic significance of a given
coronary stenosis, a pressure sensor-equipped guidewire (Pressure
wire, St. Jude Medical Inc., Little Canada, MN, USA, or PrimeWire
pressure guide wire, Philips Volcano, Rancho Cordova, CA, USA)
was advanced across the lesion. Aortic pressure was obtained from
the guiding catheter, and distal intracoronary pressure was record-
ed from the pressure sensor. All hemodynamic signals were re-
corded at baseline and during maximum hyperemia induced by a
bolus of intracoronary papaverine (20 mg for the left system and
15 mg for the right coronary artery). Pressure signals recorded on
device console (Radi Analyzer X, St. Jude Medical, or Volcano S5
console or Combo Map, Philips Volcano) were extracted from the
digital archive and analyzed offline after the procedure. FFR was
calculated as the ratio of mean distal to mean aortic pressure dur-
ing maximum hyperemia.
IVUS and Virtual Histology IVUS Imaging
After obtaining hemodynamic measurements, an IVUS cath-
eter (Eagle Eye Gold, Volcano Corporation) was advanced over
the pressure-monitoring guide wire, and automated pullback
was performed at a speed of 0.5 mm per second. Quantitative
gray scale and virtual histology (VH)-IVUS analysis were per-
formed and reported at the site of minimum lumen area and
across the entire lesion segment according to consensus docu-
ment recommendations in interpretation and reporting VH-
IVUS parameters [22]. The external elastic membrane (EEM)
and lumen cross-sectional area (CSA) were measured. Plaque
plus media (P&M) CSA was calculated as EEM minus lumen
CSA; and plaque burden at MLA site was calculated as P&M di-
vided by EEM CSA; volumes were calculated using Simpson’s
rule. Remodeling index (RMI) was expressed as the EEM CSA at
MLA site divided by the EEM CSA at reference site. The refer-
ence site CSA was defined as the average of the most normal
looking proximal and distal segment CSAs within 5 mm to the
lesion. Positive remodeling was defined as lesion EEM-CSA/ref-
erence EEM-CSA > 1.05.
Lesion length was measured using the motorized pullback de-
vice (InVision Gold with the Model R-l00 research pullback de-
vice, Volcano Therapeutics Inc., Rancho Cordova, CA, USA). Mo-
torized pullback at a fixed speed (0.5 mm/s) allows for length cal-
culation (number of seconds × pullback speed).
The four VH-IVUS plaque components (fibrous, fibro-fatty,
dense calcium, and necrotic core [NC]) were measured in every
recorded frame in the entire diseased segment and expressed as
absolute amounts and as a percentage of plaque area or plaque vol-
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DOI: 10.1159/000508885
ume. A NC to dense calcium ratio was also calculated. VH-IVUS-
derived TCFA was defined as a lesion that meets both of the fol-
lowing two criteria in three consecutive frames: (1) focal NC-rich
lesions (> 10%) without evident overlying fibrous tissue, and (2)
percent plaque volume > 40% [17].
Statistical Analysis
Continuous variables were expressed as mean ± standard de-
viation. The χ2 test was used for comparison of frequency of
TCFA between groups. Relationships between continuous vari-
ables were examined by using Pearson correlation or linear re-
gression analysis. Relationships between FFR and features of
plaque vulnerability (TCFA, positive remodeling, and plaque
components) were examined by controlling for anatomical fac-
tors that may affect hemodynamic outcomes including IVUS
MLA, lesion length, and plaque burden by using partial correla-
tion analysis. Group means were compared by Student’s t test for
independent groups and adjusted for possible confounders
(MLA, lesion length, and plaque burden) with the use of multi-
variable analysis of covariance (ANCOVA) where appropriate.
Since the only plaque component that correlated with FFR after
controlling for potential confounders with partial correlation
was the NCV, two groups (large and small NCV groups) were
identified according to the median value of NCV (18.65 mm3).
Multivariable analysis (ANCOVA) that included MLA, lesion
length, and plaque burden as covariates was also run to compare
FFR values between these two groups. Independent predictors of
FFR, as continuous variables, were also identified using multi-
variate regression analysis. Statistical tests were performed with
the Statistical Package for the Social Sciences version 17.0 pro-
gram (SPSS Inc., Chicago, IL, USA).
Table 1. Patient characteristics
Clinical and demographical characteristics (n = 60)
Males, n (%) 51 (85)
Age, years 58.8±10.5
Body mass index 28.9±4.4
Diabetes mellitus, n (%) 30 (50)
HbA1c, % 6.7±1.5
Chronic renal disease, n (%) 9 (15)
Hypertension, n (%) 44 (73)
Dyslipidemia, n (%) 29 (48)
Smoking, n (%) 35 (58)
Stable angina, n (%) 26 (43)
Unstable angina, n (%) 34 (57)
Previous myocardial infarction, n (%) 5 (8)
Ejection fraction (echocardiography), % 59.6±7.4
PCI, n (%) 49 (70)
Angiographical characteristics (n = 70)
Coronary vessels, n (%)
LAD 36 (51)
Diagonal 1 (1.4)
Intermediate 4 (5.7)
Circumflex 12 (17.1)
RCA 17 (24.3)
Angiographic stenosis (QCA, mean), % 62.1±16.3
LAD, left anterior descending artery; PCI, percutaneous
coronary intervention; RCA, right coronary artery; QCA,
quantitative coronary angiography.
Table 2. Intracoronary hemodynamic measurements
Stable lesions
(n = 36)
Unstable lesions
(n = 34)
Total
(n = 70)
Pd/Pabaseline 0.86±0.18 0.77±0.15 0.84±16.6
Pahyperemic 93.0±19.0 98.6±15.5 95.4±19.1
Pdhyperemic 68.3±20.2 64.3±20.6 67.3±20.3
FFR 0.77±0.14 0.68±0.14 0.73±0.14
Pd, distal pressure; Pa, aortic pressure; FFR, fractional flow
reserve.
Table 3. Intracoronary ultrasonographic characteristics (n = 70)
Grey scale measurements
At the minimum luminal CSA
EEM, mm212.8±4.2
P + M, mm210.2±3.2
Plaque burden, % 78.1±7.7
MLA, mm22.94±0.8
Volumetric analysis
EEM volume, mm3188.5±25.9
Luminal volume, mm354.9±24.5
P + M volume, mm3129.2±83.5
Other grey scale IVUS data
Lesion length, mm 14.9±8.4
Attenuated plaque, n (%) 17 (24)
Reference EEM CSA, mm212.14±4.04
RMI 1.1±0.3
Eccentricity index (mean) 0.48±0.13
VH measurements
At the minimum luminal CSA
Fibrous area, %/mm255.2±14.1/4.3±2.3
Fibro-fatty area, %/mm213.5±11.7/1.1±1.1
NC area, %/mm221.2±9.0/1.7±1.1
DC area, %/mm29.0±10.5/0.6±0.5
NC/DC areas 4.7±4.3
Volumetric analysis
Fibrous volume, %/mm354.2±10.6/48.8±35.5
Fibro-fatty volume, %/mm314.3±10.8/11.8±10.7
NC volume, %/mm321.4±7.7/21.3±18.8
DC volume, %/mm39.9±9.1/8.9±10.4
NC/DC volumes 3.5±2.4
CSA, cross sectional area; MLA, minimal luminal area; EEM,
external elastic membrane; RMI, remodelling index; VH, virtual
histology; IVUS, intravascular ultrasonography; P, plaque; M,
media; NC, necrotic core; DC, dense calcium.
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Results
Patient Characteristics
Eighty-two patients with at least an intermediate coro-
nary stenosis were identified. Nine patients with prior
coronary artery by-pass surgery and 2 patients with sig-
nificant aortic stenosis were excluded. Eleven of the re-
maining 71 patients, we were unable to obtain a paired
hemodynamic and morphological data. Therefore, final
study population comprised 60 patients, with a total of 70
lesions. Patient demographics are summarized in Table 1.
Thirty-six stable lesions from 26 patients with stable
angina pectoris and 34 lesions from 34 patients with
NSTEACS were analyzed. Mean angiographic stenosis
assessed by quantitative coronary analysis was 62.1 ±
16.3%. A total of 49 lesions (70%) were treated with per-
cutaneous coronary intervention after hemodynamic and
morphological evaluation. The majority of the stenoses
evaluated in this study were located in the left anterior
descending artery (Table 1).
Hemodynamic and Ultrasonographic Findings
Hemodynamic and ultrasonographic findings are pre-
sented in Tables 2 and 3. In the entire group, the mean
FFR value was 0.73 ± 0.14. Using the established ischemic
cut-point of 0.80 for FFR, 38 lesions were classified into
ischemia-producing (hemodynamically significant) ste-
nosis group. The mean MLA was 2.94 ± 0.8 mm2. The
mean percentages of fibrous, fibro-fatty, NC, and dense
calcium volumes were 54.2 ± 10.6, 14.3 ± 10.8, 21.4 ± 7.7,
and 9.9 ± 9.1%, respectively. VH-IVUS-defined TCFA
was present in 38 of the lesions (54.3%). The mean at-
tenuated plaque angle was 115.2 ± 25.6°. In patients with
NSTEACS, the RMI was significantly higher and TCFA
significantly more frequent (Table 4). In addition, in VH-
IVUS analysis, fibrous volume was significantly lower
and fibro-fatty and NC volumes were significantly higher
in NSTEACS patients as compared with stable CAD pa-
tients (Table 4).
Table 4. Comparison of features of plaque vulnerability and VH-IVUS–defined plaque characteristics between
stable coronary artery disease (CAD) and acute coronary syndrome (ACS) patients
Stable CAD
(n = 36)
ACS
(n = 34)
p
Remodeling index 0.98±0.21 1.28±0.37 <0.001
TCFA, n (%) 14 (38) 24 (70) 0.004
At the minimal luminal area
Fibrous area mm24.86±2.43 3.9±2.2 0.09
% 56.97±15.17 54.18±13.63 0.43
Fibro-fatty area mm21.00±0.76 1.17±1.35 0.18
% 11.43±6.91 14.86±13.74 0.57
NC area mm21.47±0.96 1.91±1.28 0.10
% 20.8±9.6 22.0±8.4 0.58
DC area mm20.62±0.59 0.51±0.51 0.40
% 10.13±11.85 6.9±7.56 0.08
NC area/DC area 4.51±4.41 5.41±4.13 0.06
Entire lesion segment (volumetric analysis)
Fibrous volume mm356.14±31.77 37.38±31.35 0.033
% 51.99±11.88 38.16±7.31 0.04
Fibro-fatty volume mm39.92±9.79 14.37±11.78 0.012
% 15.45±13.08 16.78±11.4 0.072
NC volume mm316.01±14.8 27.36±20.40 0.009
% 20.23±8.78 29.26±15.75 0.034
DC volume mm38.28±11.43 9.16±8.54 0.71
% 11.25±10.97 10.29±4.22 0.21
NC volume/DC volume 3.44±3.4 3.94±3.48 0.56
TCFA, thin cap fibroatheroma; NC, necrotic core; DC, dense calcium.
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IVUS Parameters of Lesion Severity and
Hemodynamic Outcome
MLA modestly correlated with FFR (r = 0.318, p =
0.002). Indeed, correlations between FFR and lesion
length (r = –0.467, p < 0.001) and plaque burden (r =
–0.371, p = 0.002) were stronger. The relationship be-
tween lesion length and FFR (r = –0.40, p = 0.002) re-
mained significant even after controlling for MLA.
IVUS Parameters of Vulnerability and Hemodynamic
Outcome
Relationship between Vessel Remodeling and Plaque
Vulnerability and FFR
In the positively remodeled vessels (n = 34), TCFA
was more frequent (65 vs. 38%, p = 0.026), and NCV was
larger (26.15 ± 14.22 vs. 16.21 ± 8.93 mm3, p = 0.04) than
their non-remodeled counterparts. RMI showed a posi-
tive correlation with NCV across the entire lesion seg-
ment (r = 0.396, p = 0.001) (Fig.1a) and a strong negative
correlation with FFR (r = –0.477, p < 0.001) (Fig.1b).
Correlation between RMI and FFR remained significant
even after controlling for potential confounders (MLA,
plaque burden, and lesion length) (r = –0. 419, p = 0.001).
Additionally, the mean adjusted FFR value was signifi-
cantly lower in positively remodeled than non-remod-
eled vessels after controlling for potential confounders
by multivariable analysis (adjusted; 0.69 vs. 0.78, p =
0.004) (Fig.2).
Relationship between VH-IVUS-Derived Plaque
Composition and FFR
In the entire group of 70 stenoses, NC area at MLA and
NCV were the only VH-IVUS-defined plaque compo-
nents that were correlated with FFR. After controlling for
MLA, lesion length and plaque burden, correlations be-
tween FFR and NC area at MLA (r = –0.262, p = 0.038)
and NCV across the entire lesion segment (r = –0.272,
(R = 0.396, p = 0.001)
80
60
40
20
0
0.75 1.00 1.25
Compute RMI = EEMCSAp/EEMCSAref
NCV
1.50 1.75 2.0
(R = –0.477, p
< 0.001)
1.00
0.80
0.60
0.40
0.20
FFR
0.75 1.00 1.25
Compute RMI = EEMCSAp/EEMCSAref
1.50 1.75 2.00
a b
Fig. 1. Relationships between remodeling index (RMI) and necrotic core volume (NCV) across the entire lesion
segment and FFR. a The relationship between RMI and NCV. b The relationship between RMI and FFR.
0.69
0.78
0.64
0.66
0.68
0.70
0.72
0.74
0.76
0.78
0.80
1 2
FFR
RMI >1.05 RMI <1.05
(p
adj
= 0.004)
Fig. 2. Impact of positive remodeling (remodeling index [RMI] >
1.05) on FFR (adjusted mean values for FFR were provided from
multivariate analysis.
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p = 0.024) remained significant. In multivariable analysis,
which included MLA, lesion length, plaque burden, and
NCV, the group of lesions with NCV larger than the me-
dian value (18.65 mm3) had a significantly lower mean
FFR value than the group of lesions with smaller NCV
(adjusted; 0.69 vs. 0.77, p = 0.047) (Fig.3). In the multi-
variate linear regression analysis, independent predictors
of FFR were lesion length (beta = –0.482, p = 0.001), MLA
(beta = 0.324, p = 0.026), and NCV (beta: –0.303, p =
0.047) (Table 5a).
Relationship between Presence of VH-IVUS-Derived
TCFA and FFR
The group of lesions with TCFA (n = 38) had a sig-
nificantly lower mean FFR value compared to those with-
out TCFA (0.70 ± 0.13 vs. 0.79 ± 0.08, p = 0.007). Multi-
variable analysis including lesion length, MLA, plaque
burden, and presence or absence of TCFA revealed that
presence of TCFA was associated with significantly lower
adjusted mean FFR value when compared to the absence
of TCFA (0.71 vs. 0.78, p = 0.034) (Fig.4). Multivariate
linear regression analysis included the aforementioned
confounders and revealed that MLA (beta = 0.386, p =
0.011), lesion length (beta = –0.368, p = 0.016), and pres-
ence of TCFA (beta = –0.289, p = 0.039) were indepen-
dent determinants of FFR (Table 5b).
Discussion
The findings of this study suggested that plaque fea-
tures of vulnerability such as VH-IVUS-defined thin-cap
fibroatheroma, NC content, and positive remodeling may
independently contribute to the hemodynamic effect of
the coronary stenoses that are in the upper end of the in-
termediate lesion spectrum, where judging the ischemic
potential of an angiographic lesion is challenging in rou-
tine daily clinical practice.
In the literature, discrepant results have been reported
in previous invasive trials examining the possible impact
of coronary plaque composition defined by IVUS on he-
0.69
0.77
0.64
0.66
0.68
0.70
0.72
0.74
0.76
0.78 (p
adj
= 0.047)
FFR
Group 2
NCV <median
value 18.65 mm3
Group 1
NCV >median
value 18.65 mm3
0.71
0.78
0.66
0.68
0.70
0.72
0.74
0.76
0.78
0.80 (p
adj
= 0.034)
FFR
Group 1 (TCFA+) Group 2 (TCFA–)
Fig. 3. The impact of necrotic core volume (NCV) on the hemody-
namic significance of the coronary artery lesions as assessed by
FFR (adjusted mean values for FFR were provided from multivar-
iate analysis). Group 1: lesions with NCV larger than the median
value (18.65 mm3). Group 2: lesions with NCV smaller than the
median value (18.65 mm3).
Fig. 4. The influence of TCFA presence on FFR (adjusted mean
values for FFR were provided from multivariate analysis).
Table 5. Independent predictors of FFR in multivariate linear re-
gression models
βp
aModel 1. Included variables: Lesion length, minimal luminal
area (MLA), plaque burden and necrotic core volume (NCV)
Lesion length –0.482 0.001
MLA 0.324 0.026
NCV –0.303 0.047
bModel 2. Included variables: Lesion length, MLA, plaque bur-
den and thin-cap fibroatheroma (TCFA)
Lesion length –0.368 0.016
MLA 0.386 0.011
TCFA –0.289 0.039
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Plaque Vulnerability and Hemodynamic
Relevance of Coronary Artery Stenoses
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Cardiology
DOI: 10.1159/000508885
modynamic outcome [9, 23–25]. Although most of the
previous invasive studies reported that composition of
the coronary stenoses may not have a significant impact
on their hemodynamic effect, these studies [23–25] in-
cluded substantially milder angiographic stenoses com-
pared to our cohort, which might have blunted the effects
of surface properties on epicardial resistance. In this re-
gard, in the current study, negative associations shown
between NC content, TCFA, and FFR cannot be readily
explained by recognizing anatomical and physiological
parameters of lesion severity. When the physical determi-
nants of pressure drop across a stenosis are considered, it
becomes evident that minimal lumen area is one of the
most critical determinants of both the conversion of lam-
inar flow into a turbulent pattern and the pressure drop
across the stenosis according to Poiseuille’s formula [26].
Yet, in accordance with our findings, MLA was curiously
mild, and lesion length, although it is a weaker determi-
nant of pressure drop across the stenosis compared to
MLA in modified Poiseuille’s formula, showed similar
[23] or even a stronger correlations [7, 27] with FFR in
some of the studies. This suggests that other factors acting
across the length of the lesion may also contribute to the
pressure loss across a stenosis. Accordingly, our findings
showing significant independent associations between
NC and TCFA and FFR suggest that certain plaque com-
ponents may cause further frictional loss of energy by in-
fluencing structural feature of the lesion surfaces, and
may, therefore, have a considerable impact on the pres-
sure drop across the stenoses.
In a given coronary stenosis, whether ultrasonograph-
ically detectable or not, plaque disruption, erosion, or rup-
ture may influence functional severity of the stenosis by
contributing to surface roughness [6]. An individual
plaque component can contribute to an increase in steno-
sis resistance by means of generation of microturbulences
at plaque level via inducing surface irregularities and by
affecting vascular compliance. These potential mecha-
nisms may result in further loss of kinetic energy of the
blood flow and further rise in translesional pressure gradi-
ent. Accordingly, presence of ruptured plaques has been
shown to influence hemodynamic significance of a given
coronary stenosis [5]. Hence, plaque erosions, small or ul-
trasonographically undetectable plaque ruptures, and po-
tentially unruptured TCFAs with superimposed throm-
bosis may also influence the hemodynamic significance of
a stenosis. Presence of plaque rupture and/or erosion has
been demonstrated to be associated with presence of
TCFA and higher NC content [28]; however, IVUS has a
limited ability in detecting ruptured plaque. It is expected
that eroded and/or ruptured plaques would have been de-
tected significantly more frequently if optical coherence
tomography with a resolution of 10–20 μm [29, 30] had
been used in the current study. Accordingly, in a recent
study, presence of OCT-derived TCFA and reduced fi-
brous cap thickness were shown to be associated with low-
er FFR values [31]. Furthermore, in line with our findings,
studies investigating the role of computed tomography
angiography (CTA)-defined morphological features of
coronary plaques in predicting invasive and non-invasive
FFR have recently demonstrated NCV [21] and low-den-
sity non-calcified plaques (CTA surrogate for the presence
of NC) [20] to be independent predictors of FFR.
As an additional point of view, NC content may also
affect vascular wall vasodilator abilities negatively. The
stenotic vascular segment with plaques containing large
NC and extraluminal expansion with positive remodeling
may have impaired vasodilator capacity. Plaques with an
NC harbor local inflammation and may compromise bio-
availability and production of vasodilators [32, 33]. This
may lead to local endothelial dysfunction with the inabil-
ity of vascular segments with a large NC content to dilate
appropriately in response to vasodilator stimuli. Accord-
ingly, presence of NC plaques was shown to be associated
with impaired vasodilator response of epicardial coro-
nary artery segments [34]. Indeed, in the present study,
the NC content was significantly larger in positively re-
modeled vessels than their un-remodeled counterparts.
This finding was consistent with a report by Roleder et al.
[35]. This may lead to local inability of the stenotic vas-
cular segment to dilate to the same extent as the rest of the
vessel, the result of which would be a larger translesional
pressure drop and lower FFR value [19]. Consistently, in
the current trial, beside larger NC content and presence
of TCFA, higher positive RMI was independently associ-
ated with lower FFR value regardless of anatomical sever-
ity of coronary lesions. In line with our results, in studies
in which association between CTA-derived lesion mor-
phology and invasive FFR were evaluated, positive re-
modeling has been shown to independently predict FFR
[3, 36, 37]. However, in previous reports showing the cor-
relations between CTA-defined features of plaque vul-
nerability and invasive and non-invasive FFR, stenosis
severity and FFR were classified in a dichotomous fashion
[20, 21, 34]. However, the current analysis, in which both
stenosis severity and FFR were used as continuous vari-
ables, may have provided additional insights into the re-
lationship between plaque vulnerability criteria and FFR.
Taken together, the size of the NC and presence of
TCFA along with the extent of vascular remodeling may
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Cardiology
8
DOI: 10.1159/000508885
substantially contribute to dissociation of anatomical ste-
nosis severity from hemodynamic consequences by con-
tributing surface irregularity and roughness and by caus-
ing compromised vasodilation that may eventually result
in greater trans-lesional energy loss and lower FFR values.
From a clinical point of view, notably, it has been known
that plaques with NCs are the primary anatomical sub-
strate for acute myocardial infarction and sudden cardio-
vascular death [16, 17]. Our study consistently showed
that a coronary stenosis with a normal FFR has a low like-
lihood of having plaques with high-risk features. There-
fore, these aforementioned associations shown between
plaque features of vulnerability and hemodynamic out-
come can also help us understand why revascularization
may be safely deferred in lesions with FFR > 0.80 [38] and
why the event rates were significantly higher in deferred
angiographically insignificant lesions in stable CAD pa-
tients with low FFR than those with high FFR [39]. In this
respect, the benefit of FFR-guided therapy may become
evident, at least in part, based on its potential connection
with plaque vulnerability/activity shown in both stable
and unstable CAD patients in the current study.
Clinical Implications and Future Directions
Taken together, these results have several important
clinical implications. Firstly, plaque composition and
positive remodeling seem to affect the hemodynamic im-
pact of certain stenoses that are classified in the upper end
of the intermediate coronary stenoses. Since epicardial
lesion-related coronary stenosis resistance may be active-
ly influenced by many pathophysiological processes in-
cluding plaque vulnerability, evolution, inflammation,
and vascular reactivity [12, 13, 40], even a single snapshot
FFR measurement taking into account these abovemen-
tioned factors may be an extremely valuable tool to assess
the clinical significance of a certain lesion over a long
time. Secondly, if certain plaque characteristics are able
to change marginally hemodynamically insignificant
plaque into a significant one, theoretically plaque stabili-
zation by pharmacological interventions and or lifestyle
changes may convert a hemodynamically significant ste-
nosis into an insignificant one. Preventing minor rup-
tures causing plaque surface roughness or changing com-
position of an atheroma (reducing the NC content) may
tip the balance in favor of less resistance and less remod-
eling and may, therefore, increase the FFR value back to
normal. This notion hints at a new concept of hemody-
namic plaque stabilization beyond a familiar histological
plaque stabilization concept. Further studies are needed
to address this issue.
Limitations
The main limitation of this study is related to the lim-
ited resolution of VH-IVUS in detecting small ruptures
and fissures that may result in increased resistance to flow
with changing surface properties. Therefore, potential
reasons underlying the link between parameters of le-
sions’ functional significance and VH-IVUS-derived pa-
rameters of plaque vulnerability cannot be directly deter-
mined. Secondly, heavily calcified plaques may induce an
artifact regarding the classification of plaques by VH-
IVUS resulting in an increase in NC content [41]. Blood
viscosity is another fundamental determinant of pressure
drop across a stenosis. It has been previously shown that
NCV correlates with inflammatory state in patients with
non-ST elevation acute coronary syndrome [42], which
in turn may affect blood viscosity. Therefore, it would
have been clarifying to include blood viscosity in the cur-
rent study, but we were unable to measure it as a part of
our study protocol. Lastly, VH-IVUS may overestimate
TCFA prevalence. VH-IVUS studies consistently show a
higher than anticipated prevalence of TCFA in vivo [43].
In contrast, OCT has a higher sensitivity (90–92%) to
identify lipid-rich plaques [44]. The relatively high preva-
lence of TCFA found in the current study can be ex-
plained by both inclusion of unstable patients and over-
estimation by VH-IVUS.
Conclusion
This study demonstrated that for a given stenosis ge-
ometry, features of plaque vulnerability may influence the
hemodynamic relevance of intermediate coronary steno-
ses. Whether modulation of these adverse plaque charac-
teristics by pharmacological and other means may lead to
improved hemodynamics and patient outcomes needs to
be elucidated in further longitudinal studies.
Statement of Ethics
The study was conducted in accordance with the Declaration
of Helsinki, and the local ethical review board approved the study
protocol. Written informed consent was obtained from all pa-
tients.
Conflict of Interest Statement
This study was supported by the Turkish Academy of Sciences
(TUBA) (Murat Sezer).
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Plaque Vulnerability and Hemodynamic
Relevance of Coronary Artery Stenoses
9
Cardiology
DOI: 10.1159/000508885
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