(Circulation. 2000;101:491.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
The Impact of Coronary Artery Disease on the Coronary Vasomotor Response to Nonionic Contrast Media
From the Cardiac and Thoracic Department, University of Pisa; and CNR Institute of Clinical Physiology and Scuola Superiore S. Anna (R.D.), Pisa, Italy.
Correspondence to Ugo Limbruno, MD, PhD, Cardiac and Thoracic Department, Cisanello Hospital, Via Paradisa 2, 56124, Pisa, Italy. E-mail ulimbru{at}tin.it
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Abstract |
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Background—Coronary artery disease (CAD) alters the vasomotor response to a variety of pharmacological agents. We tested the hypothesis that CAD also has an impact on the coronary vasomotor response to radiologic contrast media.
Methods and Results—We performed quantitative coronary
angiography in 42 patients without angiographic evidence of CAD and 38
patients with CAD in the left coronary artery. Angiographically
smooth coronary segments (n=235) were analyzed for
changes on luminal diameters and coronary venous oxygen
saturation in response to 3 media: the nonionic dimer iodixanol, the
nonionic monomer iopromide, and the ionic agent ioxaglate. In subjects
without CAD, we assessed the effects of intracoronary
administration of the nitric oxide synthase inhibitor
NG-monomethyl-L-arginine and of the
cyclooxygenase inhibitor
indomethacin on such changes. Iodixanol induced
coronary vasodilation in subjects without CAD (8.8±8.6%,
P<0.001). Patients with CAD exhibited no significant
diameter changes in segments 
20 mm apart from a stenosis
(4.7±9.4%, P=NS) and significant constriction in
segments <20 mm from a stenosis (-3.8±4.6%,
P<0.05). Similar results were obtained with iopromide,
but no changes were found with ioxaglate. All contrast media induced
transient (<35 seconds) increases in coronary venous oxygen
saturation in all subjects. Indomethacin, but not
NG-monomethyl-L-arginine, blunted the
vasodilating effect of iodixanol and iopromide (by 80% and 76%,
respectively; P<0.001).
Conclusions—Nonionic contrast media induce a vasodilatory response in normal vessels not by a mechanism involving increased flow or endothelial nitric oxide synthesis, but rather by depending on preserved vascular cyclooxygenase activity. CAD changes normal epicardial vasodilatory response into vasoconstriction.
Key Words: contrast media • coronary disease • vasoconstriction • vasodilation • endothelium-derived factors
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Introduction |
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Achange in vessel tone is a well known side effect of angiographic contrast media. Most often a vasodilation is seen, but sometimes a vasospasm occurs. Vasodilation has been attributed to hyperosmolality, chemotoxicity, ion content of the medium, and flow-mediated changes in vascular tone.1 2 3 4 5 Coronary vasoconstriction has been observed after injection of both ionic and nonionic contrast agents.6 7 8 In experimental studies on isolated arteries, vasoconstriction has been related to chemotoxicity and/or depolarization of smooth muscle cells.9 10
It is conceivable that coronary artery disease (CAD) might interfere with the vasomotor reaction of coronary arteries to contrast agents. In fact, low concentrations of diatrizoate, a high-osmolar ionic agent, induced vasodilation in normal rabbit aortas but vasoconstriction in atherosclerotic aortas.11 Jost et al2 have shown no uniform vasomotor responses to diatrizoate in stenosed coronary segments.
We tested the hypothesis that CAD is associated with an altered vasomotor response to contrast media. Our objectives were to evaluate: (1) the effect of 3 iodinated contrast media: iodixanol (nonionic, dimeric), iopromide (nonionic, monomeric), and ioxaglate (ionic) on the dimensions of angiographically normal epicardial coronary segments in patients with normal coronary arteries and patients with CAD; (2) the relationship between the effects of contrast media on epicardial coronary artery dimensions and changes in coronary blood flow; and (3) the role of endothelial nitric oxide and cyclooxygenase in the vasomotor effect of contrast agents.
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Methods |
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Patient Selection
We enrolled 92 patients undergoing diagnostic cardiac catheterization and coronary angiography for chest pain syndrome. Forty-seven patients had entirely smooth coronary arteriograms and 45 had significant CAD, as defined by the presence of a stenosis
50% in at least 1
segment of the left coronary artery. Patients with unstable
angina, previous myocardial infarction, left ventricular
hypertrophy or dysfunction, valvular disease, or
renal insufficiency, as well as patients with isolated right CAD,
occlusive or subocclusive coronary stenoses, or diffuse
disease were excluded from the study. All medications were discontinued
48 hours before the study with the exception of low-dose (50 mg/d)
aspirin. The study was approved by the Institutional Review Committee
at Pisa University. Informed consent was obtained from each
patient.
Protocol A
This protocol was designed to evaluate the effects of contrast
media on epicardial coronary artery dimensions and on
coronary venous oxygen saturation (Figure 1A
). Patients were randomly assigned to
the iso-osmolar, nonionic, dimeric agent iodixanol (Visipaque 320,
Nycomed Imaging AS; osmolality: 290 mOsm/kg)(n=28); the low-osmolar,
nonionic, monomeric agent iopromide (Ultravist 370, Schering AG;
osmolality: 770 mOsm/kg)(n=14); or the low-osmolar, ionic agent
ioxaglate (Hexabrix 320, Guerbet; osmolality: 608 mOsm/kg)(n=18). No
significant differences in the prevalence of the main
cardiovascular risk factors were observed among the
different contrast groups (Table 1). Total cholesterol showed
a trend, within each contrast agent comparison, to be higher in the CAD
group and was significantly higher in the entire CAD group of this
protocol compared with the no CAD group (200±37 versus 178±46 mg/dL,
P<0.05).
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The first quantitative coronary angiogram (QCA-0) was performed in the 30° right anterior oblique projection and served as reference. At 50-second intervals, subsequent diagnostic or QCA angiograms were performed. QCA-1 was performed under the same conditions (angle of view, distance between the x-ray focus and the patient and between the patient and the image intensifier, table position) as in QCA-0. Differences in epicardial coronary dimensions between QCA-0 and QCA-1 were assumed to be induced by the contrast. An additional angiogram was performed again under standard conditions (QCA-2), and differences in coronary dimensions between QCA-1 and QCA-2 were assumed to be a measure of the short-term variability of coronary measurements. Finally, 200 µg of nitroglycerin were administered into the left coronary artery over a period of one minute followed by the final angiogram (QCA-3).
Selective cannulation of the coronary sinus up to the
great cardiac vein was obtained in 30 patients of protocol A.
Coronary venous oxygen saturation and hemoglobin concentration
were determined before QCA-0, and before and 15, 25, 35, and 45 seconds
after the diagnostic angiogram preceding QCA-1 (Figure 1A
). Changes in great cardiac vein oxygen saturation were
assumed to reflect changes in myocardial blood flow in the left
anterior descending coronary artery territory.
Protocol B
This protocol, summarized in Figure 1B, was designed to
examine the role of endothelial nitric oxide and
vascular cyclooxygenase in the changes induced by
nonionic agents on epicardial coronary dimensions. Twenty
patients with angiographically normal coronary arteries were
enrolled according to the same inclusion/exclusion criteria described
above. Sixty-nine segments (all segments A) were analyzed
(Table 2). After completion of
diagnostic coronary arteriography,
intracoronary infusion of isotonic saline at 1 mL/min was
started. Two quantitative left coronary angiograms, QCA-0 and
QCA-1, were performed as described in protocol A. Thereafter, the
arginine analogue
NG-monomethyl-L-arginine,
a competitive inhibitor of nitric oxide synthesis, or
indomethacin, a cyclooxygenase
inhibitor, were infused into the left coronary
artery at 50 µmol/min and 3 µmol/min,
respectively, for the rest of the protocol (infusion rate 1 mL/min).
QCA-0 and QCA-1 were then repeated. A final quantitative angiogram was
performed after intracoronary administration of 200
µg nitroglycerin (QCA-3). Differences in
epicardial coronary dimensions between QCA-0 and QCA-1 were
assumed to be contrast-induced. Patients were randomly assigned to
iodixanol or iopromide. Within each contrast group,
indomethacin or
NG-monomethyl-L-arginine
were used in an alternate fashion.
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Protocol C
This protocol was designed to evaluate the time course of
nonionic contrast-induced changes in coronary luminal
diameters. Five patients (2 female, 3 male, age 60±11 years) with
angiographically normal coronary arteries and 7 patients (2
female, 5 male, age 64±13 years) with left CAD were enrolled according
to the same inclusion/exclusion criteria as above. After completion of
the diagnostic coronary angiography, additional
heparin (2500 U) was administered and a 2.6F, 40-MHz SCIMED
intravascular ultrasound catheter was introduced over a 0.014-inch
guidewire and positioned in an angiographically normal left
coronary segment. In patients with CAD, only segments >5
mm and <20 mm apart from a significant stenosis were
evaluated. Luminal cross-sectional area, defined as the integrated area
central to the intimal leading-edge echo, was measured in basal
conditions and at various times after intracoronary injection
of 8 mL iodixanol. One or 2 segments were evaluated in each patient.
Quantitative Angiography
Study angiograms were examined by 2 investigators, and
angiographically smooth coronary segments not overlapping with
other branches and running parallel to the image plane were selected by
a consensus decision before the analysis. The analysis
of each angiogram was performed on 2 end-diastolic frames
of different cardiac cycles, and the results were averaged. Digitally
recorded frames were then analyzed with a software allowing
an automated edge-detection technique.12 One-centimeter
segments of the coronary artery were selected for measurements.
Anatomic landmarks were used to reproduce the regions of interest in
different angiograms. The angiographic catheter in the field of view
served as a scaling device and this, together with correction for
pincushion distortion, allowed the diameters to be measured as absolute
values (in millimeters). Analyzed segments were classified
according to the presence of, and distance from, a 50% diameter
stenosis in another coronary segment: (1) segments A:
angiographically normal segments without stenoses in other
coronary segments; (2) segments B: angiographically normal
segments located 20 mm from the closest stenosis; and
(3) segments C: angiographically normal segments located >5 mm
and <20 mm from the closest stenosis. Differences between
QCA-1 and QCA-2 provided an evaluation of both spontaneous short-term
variability of coronary segment dimensions and the
intraobserver variability associated with repeated measurements.
Single-segment diameter changes were considered significant with a
>95% probability if they were >1 mean+1.96SD of the difference
between QCA-1 and QCA-2. The mean change in coronary dimensions
between QCA-1 and QCA-2 was 0.050±0.039 mm (n=166). Thus, a
single segment change was considered significant if 0.13 mm.
Statistical Analysis
Data were expressed as mean±SD. The significance of changes
with respect to baseline values was tested by ANOVA for repeated
measures followed by the Bonferroni correction. The significance of
differences among groups was tested by the ANOVA followed by the
Newman-Keuls test. Comparisons between groups of CAD versus non-CAD
patients were analyzed by unpaired Student’s t
test. For dichotomous variables 
2
analysis was used (unless the expected value for a cell was
<5, in which case Fisher’s exact test was performed). Statistical
significance was assumed if a null hypothesis (2-tailed) could be
rejected at P=0.05.13
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Results |
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Effect of Contrast Media on Coronary Artery Dimensions
The average changes in the luminal diameters of segments A, B, and C after iodixanol injection are illustrated in Figure 2A
. Iodixanol induced significant
dilation of segments A (8.8±8.6%, P<0.001), no
significant changes of segments B (4.7±9.4%, P=NS), and a
slight but significant constriction of segments C (-3.8±4.6%,
P<0.05). The average increase in luminal diameter of
segments A was significantly greater than that of segments B and C, and
the increase in luminal diameter of segments B was significantly
greater than that of segments C (P<0.05 in all cases). A
vasodilatory capacity was preserved in all groups because
nitroglycerin resulted in similar dilation of segments
A, B, and C (Figure 2A). Iopromide induced changes in epicardial
coronary dimensions similar to iodixanol, ie, significant
dilation of segments A (P<0.001), no significant changes in
segments B, and significant constriction of segments C
(P<0.05)(Figure 2B). Ioxaglate injection did not
induce significant luminal diameter changes in any segment group
(Figure 2C).
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P<0.05 vs segments A. 
P<0.05 vs
segments B.
The percent of segments reacting with a significant (0.13 mm)
dilation after iodixanol or iopromide injection showed a highly
significant decreasing trend from segments A to segments C (from 69%
to 7%, P<0.001 for trend after iodixanol, and from 67% to
6%, P<0.001 for trend after iopromide), whereas a specular
trend toward increase was observed for the constrictive reactions (from
0% to 32%, P<0.01 for trend after iodixanol, and from 0%
to 31%, P=NS for trend after iopromide). On the contrary,
<10% of segments A, B, or C reacted to ioxaglate with a significant
dilation or constriction, and no evident trends were observed from
group A to C. Defining the range of normal vasomotor reactions to
iodixanol or iopromide as the mean±1.96SD of diameter changes of
segments A, 20% of segments B, and 42% of segments C showed vasomotor
responses below that range (Figure 3).
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Effect of Contrast Media on Coronary Venous Oxygen
Saturation
Iodixanol, iopromide, and ioxaglate injection resulted in a
transient increase in coronary venous oxygen saturation from
27±6% to 37±5% (n=11, P<0.01), from 28±5% to 39±7%
(n=9, P<0.01), and from 31±7% to 49±8% (n=10,
P<0.001), respectively, without significant differences
between patients with and without CAD (Figure 4). The peak increase in oxygen
saturation was significantly greater after injection of ioxaglate than
after iodixanol (P<0.05) or iopromide (P<0.05).
The time course of the increase in oxygen saturation was similar for
the 3 agents.
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Effect of NG-Monomethyl-L-Arginine
and Indomethacin on Contrast-Induced Changes in
Coronary Artery Dimensions
In patients with angiographically normal coronary
arteries,
NG-monomethyl-L-arginine at
50 µmol/min significantly reduced coronary artery
diameters by -7.7±5.5% (P<0.001). Iodixanol and
iopromide increased coronary luminal diameters to a similar
extent with or without
NG-monomethyl-L-arginine
(iodixanol: 7.8±4.9% versus 10.8±6.9%, P=NS; iopromide:
8.4±6.1% versus 9.4±7.0%, P=NS)(Figures 5A and 5B).
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Indomethacin infusion at 3 µmol/min did
not induce coronary luminal diameter changes (Figures 5A and 5B). Iodixanol increased coronary luminal diameters by
9.4±7.5% (P<0.001) and by 2.5±4.7% (P=NS) in
the absence and presence, respectively, of indomethacin
(Figure 5A). Similarly, iopromide increased coronary
luminal diameters by 6.8±5.2% (P<0.001) and 1.7±2.5%
(P=NS) in the absence and presence of
indomethacin, respectively (Figure 5B).
Therefore, indomethacin significantly reduced the
vasodilating effect of iodixanol and iopromide by 80%
(P<0.001) and 76% (P<0.001), respectively.
Time Course of Iodixanol-Induced Changes in Coronary
Artery Dimensions
Dilation of segments A was maximal 40 seconds after iodixanol
injection and still significant at 60 seconds. The
vasoconstrictive response of segments C to iodixanol
was slightly right-shifted with respect to the dilation of segments A
(peak at 60 seconds, return to baseline at 180 seconds; Figure 6).
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Discussion |
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The main findings of this study are that: (1) nonionic contrast media iodixanol and iopromide exert different vasomotor effects on angiographically normal coronary segments of patients with CAD and patients with normal coronary arteries; (2) the distance between the coronary segment and a stenosis has an impact on the segment’s vasomotor reaction to contrast, ie, the nearer the stenosis the more likely the vasoconstriction (and the more unlikely the dilation) of the segment; (3) the ionic agent ioxaglate has no effect on epicardial coronary dimensions; (4) the 3 media induce significant hyperemia regardless of the effect on the epicardial arteries; and (5) cyclooxygenase inhibition, but not inhibition of nitric oxide synthesis, markedly attenuates the vasodilating effect of the nonionic contrast agents on normal epicardial coronary arteries.
This is the first human study demonstrating that iodinated contrast agents elicit divergent vasomotor reactions in atherosclerotic and normal coronary arteries. Interestingly, the altered vasomotor response was present at the level of angiographically smooth-appearing coronary segments of patients with CAD.
The mechanism(s) responsible for the divergent vasomotor responses of
normal and diseased coronary arteries to nonionic agents is
(are) unknown. Iodixanol is an iso-osmolar (290 mOsm/kg), dimeric,
nonionic contrast agent whereas iopromide is a low-osmolar (770
mOsm/kg), monomeric, nonionic agent. This suggests that the effects
seen were not linked to a specific characteristic of a particular
molecule or to hyperosmolality (iodixanol is actually iso-osmolar with
plasma), but rather to more general properties of nonionic contrast
media. Previous experimental and clinical studies have shown that
several stimuli, such as the intracoronary administration of
acetylcholine or serotonin, the cold pressor test, dynamic
exercise, and increased blood flow, may all cause quantitatively and/or
qualitatively different vasomotor effects on epicardial
coronary arteries in patients with CAD compared with control
subjects.14 15 16 17 18 19 20 Vasoactive agents such as
serotonin or acetylcholine elicit divergent vasomotor
effects on normal and atherosclerotic coronary arteries through
a direct vasoconstrictive effect on medial smooth
muscle cells and an endothelium-mediated
vasodilation.14 16 17 19 The
endothelium-mediated effect predominates in normal
coronary arteries, whereas it becomes blunted or absent in
patients with CAD. Karstoft et al9 demonstrated that
iodixanol and iotrolan (both nonionic agents), but not ioxaglate, have
a strong direct vasoconstrictive effect on isolated
coronary arteries. The mechanism responsible for the
vasoconstriction was found to be due to a depolarizing effect of the
nonionic agent on smooth muscle cells.9 21 The direct
vasoconstrictive effect of nonionic agents might be
counteracted in normal coronary arteries by an
endothelium-dependent, flow-mediated dilation. In fact,
vasodilation of normal epicardial coronary arteries has been
observed during increases in coronary blood flow and a loss of
this flow-mediated, endothelium-dependent dilation
occurs early in the development of coronary
atherosclerosis.19 20 An increase in
coronary blood flow immediately after the intracoronary
injection of ionic or nonionic contrast agents has been documented in
previous investigations1 2 22 and is confirmed in our
study by the increase in coronary venous oxygen saturation
(Figure 4). The short phase-lag between peak hyperemia
and maximal epicardial vasodilation, occurring 15 (Figure 4) and
40 seconds (Figure 6), respectively, after nonionic contrast
injection, might be the time required for transduction of the flow
signal into the activation of the epicardial vasodilatory
mechanism(s).23 Nevertheless, ioxaglate induced changes in
coronary venous oxygen saturation that were even greater than
those induced by iodixanol or iopromide (Figure 4) without
effects on epicardial coronary dimensions. Therefore, changes
in coronary blood flow are not likely to be involved in the
differential effects of various contrast media.
Endothelial control of vascular tone occurs through a
host of vasodilators, including nitric oxide, prostacyclin, the
endothelium-derived hyperpolarizing factor, or
vasoconstrictors such as endothelins.24 25 26 27 Thus, the
epicardial vasodilatory effect of nonionic media in subjects without
CAD may occur through enhanced availability of vasodilators or
decreased production of vasoconstrictors. We demonstrate that
the infusion of
NG-monomethyl-L-arginine did
not prevent the vasodilating effect of nonionic agents on normal
epicardial coronary arteries (Figures 5A and 5B),
indicating the involvement of mechanism(s) other than the stimulation
of nitric oxide synthesis and/or release. Conversely, a product of
vascular cyclooxygenase activity, such as
prostacyclin or the still elusive endothelium-derived
hyperpolarizing factor, may play a role in the vasodilatory effect of
nonionic contrast media because vascular
cyclooxygenase inhibition by intracoronary
indomethacin (likely more active than the weak baseline
inhibition by oral low-dose aspirin) markedly attenuated the epicardial
coronary vasodilation induced by iodixanol or iopromide
(Figures 5A and 5B).
Finally, the low-osmolar, ionic agent ioxaglate was surprisingly free of effects on epicardial coronary dimensions, although it was able to increase coronary blood flow. This result was unexpected because diatrizoate, another ionic agent, has a strong vasodilating effect on normal epicardial coronary arteries.1 2 The different vasomotor efficacy of ioxaglate (our findings) and diatrizoate (previous findings) does not seem simply attributable to the different osmolality of the 2 agents (608 mOsm/kg versus 2070 mOsm/kg) because iodixanol, hypo-osmolar with respect to ioxaglate (290 mOsm/kg), still has a significant vasodilating effect on normal epicardial coronary arteries.
Study Limitations
A short attempt to obtain selective coronary sinus
cannulation was performed in 48 consecutive patients of protocol A.
Because the success rate of this procedure was only 63%, patient
selection might have occurred, thus introducing a bias in the oxygen
measurement data. No significant differences were observed in age, sex,
and vascular risk factors distribution between patients with and
without coronary venous oxygen measurements (data not
shown).
The higher cholesterol levels in atherosclerotic patients of protocol A raises the possibility that the altered epicardial coronary vasomotor response to nonionic media reflects a direct effect of LDL cholesterol on the vascular vasomotility; alternatively, changes in vasomotility might represent the first signal of an atherosclerotic involvement of the vessel wall.
Clinical Implications
The vasoconstrictive response in atherosclerotic
segments might contribute to the development of arterial
thrombosis. There is an ongoing debate on whether nonionic contrast
media may favor thrombosis, especially in the setting of PTCA, and this
is mostly attributed to the lesser antiplatelet and anticoagulant
properties of nonionic versus ionic media. An additional
vasoconstrictory effect on the site of exposure of highly thrombogenic
material, such as on the vascular surface of a balloon-ruptured plaque,
might favor this occurrence. Moreover, it is possible that the above
mentioned vasoconstrictory effect might itself favor myocardial
ischemia in the presence of severe stenoses. In our
study, we did not observe symptoms or clear-cut electrocardiographic
signs of ischemia after nonionic contrast injection, but this
might be due to the exclusion of patients with subocclusive
stenoses or diffuse disease, and this issue now deserves
further attention.
Our findings suggest that contrast-induced vasoconstriction may last
long enough to provide an erroneous impression of the severity of
underlying CAD. This is likely to occur because the interval between 2
consecutive diagnostic angiograms is usually shorter than
the 180 seconds required for a complete return to baseline dimensions
(Figure 6). This also sheds some skepticism on the within- and
between-study comparability of quantitative angiographic data obtained
in different invasive laboratories not standardizing the use of
contrast medium. Finally, this knowledge of the impact of
atherosclerosis on the coronary vasodilatory
effects of nonionic contrast media might allow for development of a
tool for the assessment of concealed (ie, nonangiographically visible)
coronary atherosclerosis in a somewhat more
practical way than through the intracoronary administration of
exogenous substances.
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Acknowledgments |
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The authors wish to thank Stefano Taddei, MD, for help in the selection of doses of inhibitors used in this study.
Received May 17, 1999; revision received September 7, 1999; accepted September 15, 1999.
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