Coronary Heart Disease
Volume 59 Number 5
The Contrast Media Iohexol Causes
Vasoconstriction of the Proximal
Left Anterior Descending
Coronary Artery: Implications for
Appropriate Stent Sizing
Robert V. Kelly, MD, Michael J. Gillespie, MD, Mauricio G. Cohen, MD,
David P. McLaughlin, MD, E. Magnus Ohman, MD, and George A. Stouffer, MD
The effect of the contrast agent iohexol on reference
vessel size in patients with proximal left anterior
descending disease is unknown. Quantitative coronary
angiography and intravascular ultrasound were per-
formed in 15 patients with atherosclerotic disease of
the proximal left anterior descending. Mean proximal
reference vessel diameter was 2.95 ± 0.59 mm with
quantitative coronary angiography and 4.65 ± 0.66 mm
with intravascular ultrasound (P < .05). Intracoronary
injection of iohexol resulted in a significant decrease in
intravascular ultrasound-measured proximal reference
U
ndersizing of intracoronary stents is associated
with an increased risk of major adverse cardiac
events (MACE), including in-stent restenosis
and stent thrombosis.1-4 The majority of intracoronary
stents are sized based on angiographically determined
diameter of a reference segment of artery. This method
is remarkably effective; however, several studies have
found significant differences in coronary artery diame-
ter as measured by quantitative coronary angiography
(QCA) as compared with intravascular ultrasound
(IVUS). For example, Moussa et al5 examined 382
lesions in 334 patients and found a mean reference
vessel diameter (RVD) by QCA of 3.0 ± 0.59 compared
From the Department of Medicine, Division of Cardiology,
University of North Carolina, Chapel Hill (RVK, MJG, MGC,
DPM, GAS), and Department of Medicine, Division of
Cardiology, Duke University, Durham (EMO), North Carolina.
Address correspondence to: George A. Stouffer, MD, Division of
Cardiology, University of North Carolina, Chapel Hill, NC
27599-7075; e-mail: rstouff@med.unc.edu.
574
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Angiology
October/November 2008 574-580
© 2008 SAGE Publications
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vessel diameter from 4.65 ± 0.66 mm to 4.47 ± 0.68
mm (P = .002). Vasoconstrictive response to iohexol in
the proximal reference vessel ranged from −0.04 mm
to 0.5 mm with a mean of 0.18 ± 0.16 mm. This study
shows that iohexol can cause significant vasoconstric-
tion of the proximal reference vessel in patients with
severe disease involving the proximal left anterior
descending.
Keywords: contrast media; vasoconstriction; stent;
left anterior descending coronary artery
with mean RVD by IVUS of 3.93 ± 0.68 mm. These
data increase the possibility that angiography as a tech-
nique may underestimate the size of the reference ves-
sel in some patients.6,7
The importance of accurate stent sizing is high-
lighted in left anterior descending (LAD) interven-
tions, where the MACE rate is frequently higher
than that observed in right coronary and circumflex
arteries. Proximal location within the LAD is an
independent risk factor for restenosis with over 30%
target lesion revascularization rates following bal-
loon angioplasty and in patients undergoing bare
metal stenting.8,9 In the Coronary Angioplasty versus
Bypass Revascularization Investigation (CABRI) trial,
proximal LAD location was independently associ-
ated with a 2-fold higher restenosis rate than any
other coronary artery location.10 In the TAXUS-IV
trial, there was a trend toward higher target lesion
revascularization rates among LAD interventions
compared with right coronary artery or circumflex
lesions (13.5% vs 9.8% vs 8.4%, P = .26).11
 The Contrast of Media Iohexol In-Stent Sizing / Kelly et al
Iodinated radiographic contrast media have
well-known vasoactive effects but whether this
affects angiographic sizing of intracoronary stents is
unknown.12 Iohexol, an iodinated, water-soluble,
nonionic monomeric contrast media, is widely used
in percutaneous coronary interventions (PCI), and
this study examined whether iohexol causes vaso-
constriction of the proximal LAD in patients with
atherosclerotic disease.
Materials and Methods
Procedure
This is a single-center observational study. A total of
15 patients with proximal LAD disease who were
referred for PCI were included. The protocol was
approved by the institutional review board, and all
patients gave informed consent.
A guide catheter was placed in the left main coro-
nary artery using standard techniques, intracoronary
nitroglycerin was administered, and angiography per-
formed in multiple views. Lesion lumen diameter was
measured using QCA with computer-assisted auto-
mated edge detection algorithm (Toshiba, Tokyo, Japan).
With the outer diameter of the contrast media filled
catheter as calibration, the lumen diameter in diastole
was recorded. The reference diameter was averaged
from 5-mm long angiographically normal segments
proximal and distal to the lesion; when a normal prox-
imal segment could not be identified (eg, ostial lesion
location), only a distal segment was analyzed. Mean
vessel diameter was calculated as (minimal vessel
diameter + maximum vessel diameter)/2.
Intravascular ultrasound imaging was performed
with an electronic phased-array transducer (Eagle Eye;
Volcano Therapeutics, Rancho Cordova, California)
that incorporated a 40-MHz single–element beveled
transducer. All IVUS studies were performed after
administration of 100 to 200 μg of intracoronary
nitroglycerin. The ultrasound catheter was advanced
>10 mm beyond the lesion or beyond the first diag-
onal artery branch (whichever was more distal) and
a mechanized pullback to the origin of the LAD was
performed at a speed of 0.5 mm/sec and stored in
digital format. Quantitative IVUS analysis was per-
formed by computerized planimetry according to the
criteria of American College of Cardiology clinical
expert consensus document on IVUS.13 Cross-sectional
area (CSA) and lumen diameter were measured at
the level of the proximal LAD lesion and within 5
mm distal and proximal to the lesion. The proximal
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575
and the distal reference segments were the least dis-
eased image slices (largest lumen with least plaque)
proximal and distal to the lesion within the proximal
LAD. An imaging run was performed at baseline (≥3
min after any exposure to iohexol) and then repeated
during intracoronary injection of iohexol.
Fractional flow reserve (FFR) was determined
using a 0.0014-inch wire with a pressure transducer
(Smartwire, Volcano Therapeutics). The FFR was
measured at baseline and then following injection of
adenosine 30 μg (ADO 30), adenosine 60 μg (ADO
60), iohexol 10 mL, and a mixture of 5 mL of iohexol
and ADO 30.
Statistical Analysis
Continuous variables that were normally distributed
are presented as mean ± standard deviation (SD). A
paired t test was used to compare QCA and IVUS
measurements and to analyze respective interval
changes in lesion measurements before and after
injections of contrast media. Baseline and postiohexol
measurements obtained with IVUS were compared
using scatterplots and linear regression to evaluate for
correlation. Differences in FFR were compared using
Friedman repeated measures analysis of variance
on ranks followed by Dunn’s multiple range test.
Differences were considered significant at P < .05.
Results
Patient Demographics and
Procedural Details
The study group consisted of 9 men and 6 women with
a mean (SD) age of 64 ± 12 years undergoing PCI of
the proximal LAD. Diabetes mellitus, hypertension,
smoking, and hyperlipidemia were present in 3, 9, 8,
and 12 patients, respectively. A total of 7 patients pre-
sented with an acute coronary syndrome, and 8
patients had chronic stable angina. The mean percent
stenosis on QCA was 73% ± 12%, and all patients were
treated by implantation of drug-eluting stents in the
proximal LAD with the median size of 3.5 × 20 mm.
In 7 patients, intracoronary stents were placed in
other coronary arteries during the index procedure but
after the LAD was studied (circumflex in 3 patients,
diagonal in 2 patients, right coronary artery in 1
patient, and ramus in 1 patient). Creatine kinase-MB
level measured in the morning after the procedure was
elevated in 6 patients (mean ± SD in 15 patients was
5.8 ± 2.9 ng/mL with a range from 1.9-11.3 ng/mL).
576 Angiology / Vol. 59, No. 5, October/November 2008
Figure 1. Comparison of RVD in the proximal LAD as deter-
mined by QCA and IVUS. Mean RVD is presented in panel A.
Minimum and maximum RVD refer to the smallest and the
greatest diameter as measured in any view (by angiography) or
any cross section (by IVUS). LAD indicates left anterior
descending; QCA, quantitative coronary angiography; IVUS,
intravascular ultrasound; RVD, reference vessel diameter.
The average mean RVD proximal to the lesion
was 2.95 ± 0.59 mm by QCA (Figure 1). The diame-
ter of the proximal LAD was significantly larger when
determined by IVUS with an average mean RVD of
4.65 ± 0.66 mm (P < .001 when compared with
QCA). There was no correlation between mean RVD
determined by QCA and mean RVD determined by
IVUS (P = .90). Maximal RVD and minimal RVD
were also significantly larger when measured by
IVUS compared with QCA (Figure 1). The IVUS-
determined diameter was larger than QCA-determined
diameter in 14 of 15 patients (93%).
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Figure 2. Effect of iohexol on LAD diameter as determined by
IVUS. The MLD is shown in A and RVD is shown in B. Each point
represents a single patient at baseline (precontrast) and during
administration of iohexol (postcontrast). Linear regression lines
with 95% CI are plotted. LAD indicates left anterior descending;
IVUS, intravascular ultrasound; MLD, minimal lumen diameter;
RVD, reference vessel diameter; CI, confidence interval.
Effect of Iohexol on Lumen Diameter
The effect of intracoronary injection of iohexol on
minimal lumen diameter (MLD) as measured by
IVUS is shown in Figure 2. In 3 patients, the lesion
was too severe to enable the passage of the IVUS
probe prior to intervention. In these patients, bal-
loon angioplasty with a 1.5- or 2.0-mm balloon was
performed at low pressures prior to IVUS. There was
a significant reduction in MLD with iohexol injec-
tion from 2.30 ± 0.18 mm to 2.16 ± 0.24 mm (P =
.002) with a corresponding reduction in CSA from
4.13 ± 0.53 mm2 to 3.76 ± 0.78 mm2 (P = .005). The
IVUS-determined MLD at baseline and follow-
ing iohexol administration were highly correlated
 The Contrast of Media Iohexol In-Stent Sizing / Kelly et al
Figure 3. Effect of iohexol on RVD and CSA. Minimum RVD,
maximum RVD, and mean RVD (mean ± SD) for proximal ref-
erence vessel are plotted at baseline (precontrast) and during
administration of iohexol (postcontrast; A). IVUS-measured
CSA at the site of MLD (lesion) and in the proximal and the dis-
tal reference vessel is shown in B (*P ≤ .005 compared with
baseline [precontrast]). RVD indicates reference vessel diame-
ter; CSA, cross-sectional area; IVUS, intravascular ultrasound;
SD, standard deviation; MLD, minimal lumen diameter.
(r = 0.69, P < .005), but the slope of the linear
regression line was less than 1.0 (Figure 2A).
Iohexol injection was also associated with a
reduction in RVD and CSA in the proximal and the
distal reference vessels. Proximal to the lesion, RVD
decreased from 4.65 ± 0.66 mm to 4.47 ± 0.68 mm
(P = .0007; Figures 2B and 3A) and distal to the
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577
Figure 4. Variation in vasoconstrictive response of LAD reference
vessel to iohexol. Variation in the amount of vasoconstriction in
the 15 patients in this study. LAD indicates left anterior descending.
lesion RVD decreased from 3.83 ± 0.48 to 3.64 ±
0.48 mm (P = .0005). Proximal to the lesion, mean
CSA was reduced from 17.2 ± 4.7 mm2 to 15.5 ± 3.8
mm2 (P = .0002) with iohexol injection, whereas dis-
tal to the lesion the mean CSA was reduced from
11.8 ± 2.7 mm2 to 10.5 ± 2.8 mm2 (P = .0006) after
iohexol was injected (Figure 3B).
A reduction in RVD ≥ 0.1 mm was observed in
10 (66%) patients with the maximum observed
effect being 0.5 mm (Figure 4). The other 5 patients
had essentially no response to iohexol (range −0.04
to 0.05 mm). Vasoconstrictive response to iohexol
was similar in patients with acute coronary syn-
dromes (0.11 ± 0.14 mm) and stable angina (0.25%
± 0.16%; P = .10). Similarly, there was no correlation
between the vessel size and the amount of iohexol-
induced vasoconstriction. Neither IVUS-determined
mean distal RVD (P = .86) nor IVUS-determined
mean proximal RVD (P = .89) correlated with the
vasomotor response to iohexol. There was a trend
toward greater vasoconstriction with smaller RVD by
QCA (r = −0.45, P = .09).
Interestingly, 4 of 6 women in the study did not
show a vasomotor response to iohexol, whereas only 1
of 9 men had no response. Given the limitations of the
small sample size, vasoconstrictive response was sig-
nificantly more pronounced in men than in women
(0.25 ± 0.15% vs 0.08 ± 0.12%; p = 0.03).
Effect of Iohexol on FFR
The FFR (mean ± SD) was 0.81 ± 0.15 at baseline and
decreased to 0.71 ± 0.15 following intracoronary
578 Angiology / Vol. 59, No. 5, October/November 2008
Figure 5. Effect of iohexol on FFR. The FFR as measured at
baseline, following stent placement (poststent) and following
administration of 10 mL of iohexol (contrast), ADO 30, ADO
60, and a mixture of 5 mL of iohexol and ADO 30 (ADO + Con).
(P < .001 for significant differences between groups using
Friedman repeated measures analysis of variance on Ranks [the
poststent group was excluded from the analysis] a?P < .05 by
Dunn’s multiple range test compared with baseline). FFR indi-
cates fractional flow reserve; ADO, adenosine.
administration of iohexol (P < .05 vs baseline; Figure 5)
and 0.70 ± 0.15 following intracoronary administra-
tion of ADO 30 (P < .05 vs baseline and P = NS vs
iohexol). The FFR did not change with a doubling of
the dose of ADO (FFR = 0.70 ± 0.15 with either
ADO 30 or ADO 60), consistent with prior studies
showing that ADO induces maximal coronary hyperemia
with the doses used in this study.14 Administration of
a mixture of ADO and iohexol elicited an FFR,
which was the same as observed with either agent
alone, demonstrating that they do not have additive
effects on FFR.
Following stent placement, the median value of
ADO-induced FFR was 0.98 ± 0.02.
Discussion
In this study of 15 patients, the lumen diameter of
the proximal LAD was significantly smaller when
determined by QCA compared with IVUS. A portion
of the difference in lumen diameter and CSA as
determined by these 2 techniques was due to iohexol-
induced vasoconstriction of the proximal LAD in
patients with atherosclerotic disease. The vasocon-
strictive effect of iohexol was apparent both in the por-
tion of the proximal LAD with overt atherosclerotic
disease and the portion of the vessel that appeared
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normal on angiography. Since the diameter of an
intracoronary stent is frequently chosen based on
angiographic size of the proximal or the distal refer-
ence vessel, these data suggest that iohexol-induced
vasoconstriction may potentially contribute to under-
sizing of coronary stents and may partially explain the
increased target lesion revascularization rates in
LAD interventions reported in prior studies.10
Our findings of a significant difference between
IVUS-determined and QCA-determined diameter of
the proximal LAD are consistent with prior studies,
which have examined other portions of the coronary
anatomy.5,15-18 The difference observed in the study
by Moussa et al5 of 382 lesions in 334 patients was
the same magnitude as observed in the present
study. The 3 angiographic predictors of a significant
difference between QCA and IVUS measurements
by univariate analysis in that study were proximal
location, vessel diameter > 3 mm, and involvement
of the LAD. Factors that have been shown to affect
the correlation between IVUS-determined and
QCA-determined diameters in other studies include
the extent of disease and eccentricity of lesions.7
The etiology of the difference between the 2 imag-
ing modalities has not been clearly defined although
Moussa et al5 speculated that the difference between
IVUS and QCA was due to inadequate identification
of a normal segment on angiography and compensa-
tory remodeling at the lesion site. Results of the
present study show that angiographic contrast media-
induced vasoconstriction may also play a role in caus-
ing variations in lumen dimensions as determined by
QCA and IVUS.
The clinical significance of the difference in
lumen dimensions between imaging techniques is
unclear. Four studies that used a randomized, con-
trolled design to evaluate the use of routine IVUS
during coronary stent implantation found that the
use of IVUS consistently resulted in achievement of
a larger MLD and/or stent CSA. In the Thrombocyte
Activity Evaluation and Effects of Ultrasound Guidance
in Long Intracoronary Stent Placement (TULIP),
patients randomized to IVUS-guided stenting had
significantly lower restenosis rates at 6 months
(45% vs 23%, P = .008).15 In the Optimal Coronary
Ultrasound (OPTICUS) trial18 and the Restenosis
After IVUS-Guided Stenting (RESIST) trial,17 there
were no statistically significant differences in resteno-
sis rates between ultrasound vs angiographic guidance.
These studies had significant differences in duration
of follow-up, study design (randomization to IVUS
before or after stenting), and study population (stable
 The Contrast of Media Iohexol In-Stent Sizing / Kelly et al
vs unstable complex angiographic lesions; patients
with diabetes). Furthermore, there is no strict con-
sensus about optimal IVUS endpoints for stent
implantation. Thus, it remains controversial about
whether routine IVUS use during stent implantation
may provide benefit to specific subgroups.
Iodinated radiographic contrast media have well-
known vasoactive effects, which have been demon-
strated in arteries of rats, pigs, dogs, and humans.12
Studies in humans have found a vasodilatory response
in normal arteries and a vasoconstrictive response in
atherosclerotic arteries. For example, Limbruno et al19
found that the nonionic contrast iopromide caused a
slight but significant vasoconstriction in angiographi-
cally normal segments within 20 mm of an atheroscle-
rotic lesion (>50% diameter stenosis) but vasodilation
of angiographically normal segments further than 20
mm from an atherosclerotic lesion. This study may
have underestimated the effects of contrast media as
changes in vasomotor tone were assessed by compar-
ing angiographic dimensions immediately following
opacification of the vessel with those observed at 50
second intervals and thus any immediate effects of
angiographic contrast media would not have been
apparent. In an ex vivo study, Karstoft et al20 found
that iohexol caused significant vasoconstriction (mean
change of 26%, range 11%-45%) of rabbit coronary
artery segments maintained in organ culture. The con-
strictive effect was transient with duration propor-
tional to the strength of the constriction.
The FFR is defined as the maximal blood flow to
the myocardium divided by the theoretical normal
maximal flow in the same distribution and thus rep-
resents the fraction of the normal maximal myocar-
dial flow that can be achieved despite a coronary
stenosis. The FFR, when measured under condi-
tions of maximal coronary hyperemia, has been
shown to reliably indicate the functional signifi-
cance of coronary stenosis in diverse patient popula-
tions, under various conditions and independent of
any effect of contrast media on vasomotion.21 Our
finding that ADO, iohexol, and ADO + iohexol had
similar effects on FFR demonstrates that iohexol
increased coronary flow to a level similar to that
observed with ADO in this population with proximal
LAD disease. In previous work, de Bruyne et al14
compared the effects of various contrast media on
FFR in 21 patients with isolated stenosis in various
parts of the coronary tree (6 of 21 patients had LAD
lesions). The FFR was reduced to a similar extent
with either 20 or 40 μg of intracoronary ADO, similar
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579
to our findings comparing 30 and 60 μg of intracoro-
nary ADO. de Bruyne et al14 found that FFR was
reduced with 6 mL of iohexol although not to the
extent observed with ADO. In an earlier study,
Tatineni et al22 had shown that injection of 4 to 6
mL of iohexol had increased mean coronary flow
velocity by 118%. In this study, iohexol increased the
coronary flow to a similar extent as nitroglycerin but
less than papaverine.
This study has several limitations including the
small number of patients enrolled (n = 15) and the
heterogeneous clinical presentations (7 patients with
acute coronary syndromes and 8 patients with chronic
stable angina). In addition, this study was not designed
to compare responses in normal versus atherosclerotic
arteries and thus vasomotor responses to iohexol in
nondiseased arteries were not measured. Lastly, this
study did not characterize the time course of vasocon-
striction in response to iohexol nor did this study exam-
ine whether there was a cumulative effect of repeated
exposure to contrast. To minimize the influence of tem-
poral factors in vasomotor responses, iohexol was
administered continuously during IVUS pullback.
Conclusion
Iohexol causes proximal vessel vasoconstriction and
dilatation of the microvasculature in patients with
severe atherosclerotic disease of the proximal LAD.
In this study, 5 (33%) patients had a vasoconstrictive
response to iohexol of ≥0.25 mm demonstrating that
in some patients with proximal LAD disease, iohexol-
induced vasoconstriction could potentially result in
undersizing of intracoronary stents. Further studies
are needed to determine whether the amount of con-
trast media-induced vasoconstriction varies with the
type of vessel, the severity of disease, the agent used,
or the patient characteristics.
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