(Circulation. 1995;92:2087-2094.)
© 1995 American Heart Association, Inc.
Articles |
Quantitative Assessment of Coronary Vasoreactivity in Humans In Vivo
Importance of Baseline Vasomotor Tone in Atherosclerosis
From the Department of Internal Medicine IV, J.W. Goethe-University, Frankfurt, Germany.
Correspondence to Dr V. Schächinger, Division of Cardiology, Department of Internal Medicine IV, J.W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
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Abstract |
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Background Disturbances in vasomotor tone are closely linked to the development of atherosclerosis and play an integral part in the pathophysiology of myocardial ischemia in patients with coronary artery disease. Currently, evaluation of coronary vasomotor tone relies on assessment of luminal changes in response to vasoactive stimuli by quantitative angiography. Assessment of luminal changes, however, may be misleading because of the effects of geometric magnification induced by atherosclerotic wall thickening and differences in basal tone, which may obscure potential effects of vasoactive stimuli.
Methods and Results Combining angiographic measurements of luminal changes with measurements of coronary wall architecture determined by intracoronary ultrasound, we calculated absolute coronary arterial vasomotor tone in 34 patients with angiographically normal or "minimally diseased" coronary arteries. Epicardial artery vasodilator capacity in response to intracoronary nitroglycerin decreased significantly with increasing atherosclerotic wall thickening. An inverse relation existed between local atherosclerotic plaque load and nitroglycerin-induced changes in vasomotor tone (r=-.65, P<.0001) regardless of potential systematically operative factors. At the same time, basal vasomotor tone significantly decreased with increasing local atherosclerotic wall thickening (r=-.38, P=.004). The vasomotor effects of acetylcholine, an endothelium-dependent vasodilator, were inversely related to wall thickening only in segments with very minor degrees of atherosclerosis, whereas no such relation was observed for epicardial artery segments with more advanced atherosclerotic wall thickening. In these segments, however, vasoreactivity to acetylcholine was closely correlated with basal vasomotor tone (r=-.62, P=.0002).
Conclusions Atherosclerosis is associated with impairment of the vasodilator response to both nitroglycerin and acetylcholine in epicardial arteries in vivo. Basal vasomotor tone appears to be the primary determinant of the altered coronary vasoreactivity in response to vasoactive stimuli.
Key Words: coronary disease • vasomotor tone • acetylcholine • ultrasonics • atherosclerosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The coronary arterial vessel wall is an active, integrated organ capable of modulating its tone, thereby affecting blood flow regulation of the coronary vasculature. The actual tone of a vessel segment is determined by the net effect of vasoconstricting and vasodilating stimuli originating from the autonomic nervous system, by humoral factors, and by vessel wall–derived vasoactive substances.1 An imbalance of this system might contribute to myocardial ischemia caused by the predominance of vasoconstricting stimuli. In addition, failure of atherosclerotic vessel segments to dilate may prevent compensatory enlargement to preserve luminal diameter despite an increase in plaque volume, a phenomenon known as vascular remodeling.2
Previous studies assessing vasomotor responses of coronary
arteries in humans were performed with angiography to measure the
luminal changes of the artery in response to various stimuli. However,
luminal changes do not adequately reflect true vasoreactivity of an
arterial segment. The reason is that a thickened
arterial wall will lead to a geometric magnification of a
given shortening of the entire arterial circumference,
resulting in an enhanced luminal change compared with a segment with a
thin arterial wall undergoing the same shortening of the
outer circumference (Fig 1
).3
Atherosclerosis is in general a diffuse disease, and
vascular remodeling may further obscure the extent of atherosclerotic
wall thickening.4 In addition and probably even more
importantly, unlike experimental studies in which vessel segments are
preconstricted to a comparable level to assess the effects of
vasorelaxing stimuli, coronary arteries in vivo have a basal
tone, which may obscure potential vasomotor effects of vasoactive
stimuli. Thus, the clinical observations of coronary vasomotor
responses assessed by angiography may be misleading because of not only
the effects of geometric magnification but also the differences in
basal vasomotor tone.
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Thus, the aim of this study was to calculate absolute coronary arterial vasomotor tone regardless of the extent of atherosclerotic wall thickening. For this purpose, we combined angiographic measurements of luminal changes with measurements of arterial wall architecture determined by intracoronary ultrasound. Because disturbances in the regulation of vasomotor tone are closely linked to the development of atherosclerosis, the model was then applied to evaluate the effects and potential determinants of local atherosclerotic wall thickening on the vasodilatory capacity in response to nitroglycerin and acetylcholine, which has been shown to induce paradoxical vasoconstrictor responses in atherosclerotic coronary artery segments.
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Methods |
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Calculation of Vasomotor Tone
To assess the vasoreactivity of a given arterial segment, it is essential to know luminal dimensions and the local extent of wall thickening. Combining angiographically determined luminal measurements with ultrasound-derived dimensions of the arterial wall provides the potential to express vasomotor tone as a function of the outer arterial circumference, which is independent of local arterial wall thickness. Assuming that the vascular wall is incompressible, the following variables were determined (calculation shown in the "Appendix" and illustrated in Fig 2
).
Nitroglycerin-induced vasodilator capacity was
calculated as the percent increase in outer arterial
circumference from baseline to maximal dilation (after
nitroglycerin injection). Total vasomotor range was
calculated as the percent reduction of outer arterial
circumference from maximal dilation to maximal constriction (complete
occlusion of the luminal area). Baseline vasomotor tone was determined
to be the position of baseline arterial dimensions within
the total vasomotor range (calculated as the percent reduction of
arterial circumference from maximal dilation to baseline
expressed in percent of total vasomotor range).
Acetylcholine-induced vasomotor response was the calculated percent
change in outer arterial circumference from baseline to
status during acetylcholine infusion (the luminal area during
acetylcholine infusion was calculated according to Equations 1 and 4 in
the "Appendix"; acetylcholine-induced vasomotor response was
subsequently calculated according to Equations 5 through 10).
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Patient Population
The model was applied to 34 patients undergoing routine
diagnostic cardiac catheterization. The
mean age was 54±7.9 years; 8 patients were women. No patient had
hemodynamically significant stenoses within the
left anterior descending coronary artery, the vessel under
study. Patients with unstable angina pectoris, recent myocardial
infarction, a clinical history of variant angina, valvular
heart disease, clinical evidence of heart failure, and diabetes
mellitus were excluded.
Study Protocol
Vasoactive medications, including calcium channel blockers,
angiotensin-converting enzyme inhibitors,
and long-acting nitrates, were withheld at least 24 hours before
cardiac catheterization. No patient received
ß-adrenergic blockers within 48 hours of the beginning of the
study. Coronary angiography was performed by a standard
percutaneous femoral approach with an 8F guiding
catheter introduced into the left main coronary artery. After
the baseline coronary angiogram was obtained, 0.25 mg
nitroglycerin was injected into the left main
coronary artery, and a coronary angiogram was obtained
2 minutes later. In 27 patients, before the injection of
nitroglycerin, a 2.7F infusion catheter was advanced
into the proximal part of the left anterior descending artery, and 7.2
µg/min acetylcholine was selectively infused. The effects of
acetylcholine infusion on luminal areas of the epicardial
arteries were reported previously.5
As in previous studies,6 7 intracoronary infusion of acetylcholine and nitroglycerin in the doses used did not significantly affect systemic blood pressure. After the angiogram obtained after nitroglycerin infusion, the guide wire was reintroduced into the left anterior descending coronary artery to perform the intracoronary ultrasound examination.
Quantitative Coronary Angiography
The method of quantitative coronary angiography was
described previously.6 7 8 Automatic contour detection was
performed by a previously validated method with a geometric edge
differentiation technique.6 7 The accuracy and precision
of this technique and the reproducibility of serial measurements under
routine clinical conditions were established in previous
studies.6 8 Quantitative measurements were performed in 5-
to 8-mm-long straight epicardial artery segments as previously
described.5 In general, the number of segments to be
analyzed was limited to a maximum of three in the proximal and
middle portions of the left anterior descending coronary artery
per patient because the size of the arteries did not allow us to
accommodate the ultrasound catheter without flow restriction in the
more distal parts of the vessel. The segments had to be clearly defined
between the takeoff of two side branches used to identify the
corresponding ultrasound images. Tapered or curved segments were
excluded from analysis. Whenever possible, measurements were
performed in both views of the biplanar images with the takeoff side
branches used as anatomic landmarks for identification of corresponding
vessel segments, and the vessel cross-sectional area was calculated
from both views with an elliptical shape assumed. Only single-plane
analysis was performed for those coronary segments
demonstrating an overlap with other parts of the coronary tree
in one view; in those cases, vessel cross-sectional area was
calculated with a circular shape assumed.
Intracoronary Ultrasound Examination
The intracoronary ultrasound procedure was performed
as previously described.5 In brief, the
intracoronary imaging system included a 30-MHz ultrasound
transducer enclosed within an acoustic housing on the tip of a 4.3F
flexible, rapid exchange catheter (CVIS). Acquired images were
recorded on super VHS videotape for subsequent off-line
analysis. The ultrasound catheter was advanced over the
0.014-in guide wire into the midportion of the left anterior descending
coronary artery. Thereafter, the ultrasound catheter was slowly
retracted under combined intermittent fluoroscopic and continuous
ultrasound guidance. The ultrasound technician documented the positions
to relate ultrasound images to angiographic segments during
off-line analysis.
Using the protocol obtained during the examination at the time of cardiac catheterization, we selected ultrasound images by reviewing the videotape recordings and identifying the takeoff of the side branches defining the vessel segment selected for quantitative angiography. A representative single ultrasound image was selected for analysis. However, when a review of the videotape recordings revealed variations in wall thickness along the length of the selected segment, at least two or more ultrasound frames were analyzed, and a mean value was calculated for the derived parameters. Ultrasound images with extensive fibrotic or calcified deposits that obscured details of the subjacent arterial wall were excluded from analysis. The selected high-quality videotaped ultrasound sequences were digitized into a 512x512x8-bit matrix by use of an image processing computer (Kontron).
The following variables were determined. Luminal area was determined when the acoustic interface between the lumen and the intimal leading edge was traced manually to obtain the luminal cross-sectional area planimetered by the computer. Review of the dynamic imaging sequence was used routinely to facilitate measurements in the frame with optimal delineation of the blood-intima border because a continuous border was not always visible along the entire circumference in an individual frame. Adjustment for magnification was performed with a distance scale automatically recorded within each ultrasound image. Arterial area was planimetered by tracing the leading edge of the adventitia. Wall area was calculated as total arterial area minus the luminal area.9 10 To normalize for different vessel sizes, relative wall area was calculated as wall area divided by arterial area times 100, thus representing the atherosclerotic "plaque load" of an individual segment. Vessel wall thickening was defined to be eccentric if the vessel wall thickness varied by >30% along the circumference. Otherwise, the vessel wall was judged to be concentric.
Statistical Analysis
All data are expressed as mean±SD. Linear regression
analysis was used to compare vasomotor tone variables with
relative wall area. ANOVA, followed by Bonferroni's modified
t test, was used to compare the
nitroglycerin-induced vasodilator capacity between
constricting and dilating segments in response to acetylcholine.
Statistical significance was assumed if a null hypothesis could be
rejected at the P=.05 level.
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Results |
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Nitroglycerin-Induced Vasodilator Capacity
The intracoronary injection of 0.25 mg nitroglycerin did not significantly affect systolic (131±21 versus 119±20 mm Hg before and after infusion, respectively; P=.08) or diastolic (75±11 versus 70±8 mm Hg before and after infusion, respectively; P=.1) pressure but slightly increased heart rate from 70±8 to 77±7 beats per minute (bpm; P<.05). A total of 54 segments of the left anterior descending coronary artery in 34 patients were analyzed. In 20 patients, only 1 segment per patient was suitable for analysis by angiography and ultrasound. Two segments per patient were analyzed in 8 subjects, and 3 segments per patient were analyzed in another 6 subjects.
The nitroglycerin-induced vasodilator capacity varied from 0% to a maximum of 21% (6.3±4.9%). The total vasomotor range was 37±10%. The baseline vasomotor tone varied from 0% to 36% (14.5±8.5%).
Intravascular ultrasound revealed a mean absolute wall area of 7.1±3.3 mm2. The extent of atherosclerosis defined as relative wall area ranged from 18% to 68% (40±12%), and the vasomotor range of the vessel segments varied from 18% to 58% (37±10%).
Fig 3 (top) illustrates that the
nitroglycerin-induced vasodilator capacity was
inversely correlated (r=-.65, P<.0001) with the
relative wall area of the vessel segment. Thus, the local reactivity of
the vessel wall to nitroglycerin decreased with
increasing local atherosclerotic plaque load. Separate analysis
of eccentrically and concentrically thickened segments revealed similar
correlations between nitroglycerin-induced dilator
capacity and plaque load, although the regression line shifted upward
for concentrically thickened vessel segments
(y=-0.20x+13.4, r=-.52,
P=.001, n=35 for eccentric segments;
y=-0.21x+16.4, r=-.52,
P=.02, n=19 for concentric segments). In addition, baseline
vasomotor tone also decreased slightly but significantly with
increasing atherosclerotic wall thickness (Fig 3 [bottom]).
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indicates eccentric; 
, concentric.Despite the significant negative correlation between nitroglycerin-induced vasodilator capacity and increased plaque load, there was a considerable spread of data. To account for differing systemic factors acting on epicardial artery tone in different patients, the nitroglycerin-induced vasodilator capacity was related to relative wall area in individual patients in whom more than one epicardial artery segment was available for analysis, with relative wall areas differing by >7% (two times the SD of ultrasound measurement variability for relative wall area). In 7 of 9 patients fulfilling these criteria, the nitroglycerin-induced vasodilator capacity decreased with increasing wall area. Thus, the nitroglycerin-induced dilator capacity decreases with increasing local atherosclerotic plaque load regardless of potential systemically operative factors.
Acetylcholine-Induced Vasomotor Responses and Atherosclerotic
Wall Thickening
The intracoronary infusion of acetylcholine did not
affect systolic (131±21 versus 125±20 mm Hg before and after
infusion, respectively) or diastolic (75±11 versus 75±12
mm Hg before and after infusion, respectively) pressure or heart rate
(70±8 versus 67±7 bpm before and after infusion, respectively).
Fig 4 illustrates the relation between
acetylcholine-induced vasomotor responses and the extent of local
atherosclerotic plaque load of the analyzed segments. The
curvilinear relation with thin-walled vessel segments exhibited a
decrease in vasomotor tone during acetylcholine infusion, whereas
segments with atherosclerotic wall thickening demonstrated a
vasoconstrictor response to acetylcholine. Most importantly, however,
in the segments with evidence of atherosclerotic wall thickening, no
relation between percent wall area and the extent of changes in
vasomotor tone was observed. Thus, when the vasodilator effects of
acetylcholine are exhausted, no further increase in vasoconstriction is
observed. These data indicate that atherosclerotic vessel segments do
not respond by an exaggerated constriction to acetylcholine with
increasing extent of local atherosclerotic plaque load.
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However, Fig 5 illustrates that the segments
demonstrating a vasoconstrictor response to acetylcholine
simultaneously exhibited a significantly reduced
vasodilator capacity to nitroglycerin (4.5±2.8% in 30
segments constricting in response to acetylcholine versus 12.4±4.6%
in 14 segments demonstrating a dilator response to acetylcholine,
P<.0001). Most importantly, Fig 6
illustrates that the extent of vasoconstriction in response to
acetylcholine was closely correlated with baseline vasomotor tone,
whereas no such relation was observed in segments demonstrating a
dilator response to acetylcholine. Thus, with increasing plaque load,
the vasomotor response to acetylcholine is related more to baseline
vasomotor tone than to the extent of local atherosclerotic plaque
load.
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Discussion |
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Coronary vasoreactivity assessed by luminal changes through angiography does not adequately reflect true vasomotor responses because local atherosclerotic plaque load may magnify luminal changes. By defining the vasomotor response in terms of changes in the outer circumference of a vessel, one might differentiate between an enhanced vasomotor response (eg, vasospasm) and a physiological vasomotor response potentiated by local atherosclerotic wall thickening (Fig 1
). This concept, developed
by McAlpin3 about 15 years ago, is called the geometric
theory. Because measurement of atherosclerotic wall thickness was not
possible in vivo, the geometric theory was applied by use of the
luminal diameter of an arbitrarily defined reference segment to
delineate the outer arterial circumference.11
This method is not reliable, however, because any given reference
segment does not reflect true arterial outer circumference
owing to the potential of diffuse disease and vascular
remodeling.12 Intravascular ultrasound provides the ability to precisely measure atherosclerotic wall thickness in vivo.10 13 14 15 16 The present study is the first to quantify absolute vasomotor tone by combining angiographically measured luminal diameters with intravascular ultrasound–derived segmental vascular wall thickness and arterial dimensions. The results of the present study demonstrate that baseline vasomotor tone is a primary determinant of the response to vasoactive stimuli. Atherosclerotic wall thickening is associated with hyporeactivity to the vasodilator nitroglycerin, in part as a result of a decrease in baseline vasomotor tone. In addition, vessel segments exhibiting a vasoconstrictor response to acetylcholine infusion suggestive of endothelium-mediated vasodilator dysfunction also demonstrate a significantly reduced vasodilator capacity to nitroglycerin. However, the extent of acetylcholine-induced constriction is primarily a function of increased basal vasomotor tone but is not a consequence of hyperreactivity to the vasoconstrictor effects of acetylcholine with increasing atherosclerotic plaque load.
Effects of Atherosclerosis
Atherosclerosis is associated with atrophy of the
medial smooth muscle layer with ensuing loss of contractile
capacity.17 In addition, atherosclerotic lesions contain
large amounts of collagen and extracellular matrix products, which
may increase the stiffness of the vascular wall.17 Thus,
atherosclerosis profoundly affects vascular wall
architecture, with structural alterations favoring hyporeactivity in
response to vasoactive stimuli.
Moreover, atherosclerotic coronary arteries were shown to undergo a remodeling process characterized by compensatory enlargement of atherosclerotic vessel segments to preserve the luminal diameter despite an increase in the size of the atherosclerotic plaque.4 Vascular remodeling is generally viewed as an active adaptive process of structural alterations of the vascular wall that occurs in response to long-term changes in local hemodynamic conditions.18 The endothelium appears to play a central role in vascular remodeling because of its capacity to release or activate substances that influence the growth and migration of cellular elements or the composition of an extracellular matrix.2 It was postulated that the development of atherosclerotic lesions is associated with an increase in local shear stress, the tractive force on endothelial cells induced by blood flow.2 Increased shear stress induces the local generation of prostacyclin19 and nitric oxide20 by the endothelium to mediate vasorelaxation and normalize shear stress. If such functional remodeling is to be operative in humans, the baseline vasomotor tone should decrease with increasing wall thickening. Thus, baseline vasomotor tone represents the state of functional remodeling of a given coronary arterial segment. A shift of baseline vasomotor tone toward maximal dilation indicates the presence of a functional remodeling process.
Mechanisms of Altered Vasoreactivity
Experimental studies demonstrated an increased dilator response to
nitroglycerin in vessel segments denuded of the
endothelium, suggesting that nitric oxide produced by
an intact endothelium reduces the sensitivity of the
vessel wall to exogenous nitrovasodilators.21 22 Human
atherosclerotic coronary artery segments were shown to release
less endothelium-derived relaxation factor
activity23 and thus would be expected to be more sensitive
to the dilator effect of
nitroglycerin.24 25 In addition, it is
generally believed that basal coronary vasomotor tone is
increased in atherosclerotic vessel segments24 25 26 as
a result of a loss of endothelium-mediated
vasodilator functions.27 In the present study,
however, not only was there an inverse correlation between
nitroglycerin-induced vasodilator capacity and
local atherosclerotic plaque load, but baseline coronary
vasomotor tone decreased with increasing atherosclerotic plaque load.
These findings contrast with experimental observations and suggest that
failure of endothelium-mediated vasodilator
functions with increasing atherosclerotic wall thickening does not
translate into an increased vasomotor tone under baseline unstimulated
conditions. Thus, the effects of atherosclerosis in
vivo are clearly different from those of simple removal of the
endothelium.
The potential mechanisms underlying impaired
nitroglycerin-induced vasodilator capacity of
atherosclerotic epicardial arteries may include the following (Fig 7): a reduced vasodilator capacity caused by structural
(eg, smooth muscle atrophy or fibrosis of the vessel wall) or
functional (eg, an altered responsiveness to stimulators of
guanylate cyclase) alterations of the vessel wall and a
decrease in baseline vasomotor tone caused by functional remodeling.
The lack of an increased baseline vasomotor tone associated with
increased atherosclerotic plaque load appears to indicate a functional
remodeling process that becomes operative with the development of
atherosclerotic wall thickening, in analogy to the well-known
structural remodeling of atherosclerotic vessel segments.4
This hypothesis is also supported by our findings on the effects of
acetylcholine on coronary vasomotor tone.
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Segments exhibiting a constrictor response to acetylcholine also demonstrated a significantly reduced dilator response to nitroglycerin. Because both nitroglycerin and endothelium-derived relaxation factor, which presumably is released by acetylcholine,28 mediate their dilator effects through a common effector target, namely smooth muscle guanylate cyclase activity, these findings raise the question of whether the acetylcholine-induced constrictor response results, at least in part, from a reduced responsiveness of vascular smooth muscle cells to endothelium-derived relaxation factor released on stimulation. However, the segments demonstrating a constrictor response to acetylcholine also had a significantly reduced baseline vasomotor tone. More importantly, the extent of acetylcholine-induced vasoconstriction was directly correlated with baseline vasomotor tone. Thus, the extent of functional remodeling appears to be a primary determinant of the vasoconstrictor effects of acetylcholine in atherosclerotically thickened coronary artery segments. Taken together, the results of the present study suggest that the decrease in baseline vasomotor tone with increasing local atherosclerotic plaque load contributes significantly to the vasoreactivity of human epicardial arteries in vivo. However, we cannot exclude the possibility that the atherosclerosis-induced structural alterations favoring a generalized hyporeactivity to both dilatory and constricting vasoactive factors might also contribute to the observed decrease in baseline vasomotor tone in atherosclerotic vessels. Thus, further studies are required to address the mechanisms and to define potential determinants of functional remodeling of atherosclerotic human coronary arteries in vivo.
In a previous study, we reported that the degree of abnormal reactivity
to acetylcholine is closely correlated with the extent of local
atherosclerotic plaque load,5 suggesting that the extent
of atherosclerotic wall thickening is associated with the degree of
deficient endothelium-mediated vasodilation.
However, when the vasomotor response to acetylcholine is quantified by
changes of absolute vasomotor tone, as in the present study, the
correlation to arterial wall thickness is limited to
segments with minor degrees of atherosclerotic wall thickening. In
contrast, no relation between acetylcholine-induced vasomotor
change and atherosclerotic plaque load could be observed for
coronary segments with larger amounts of
atherosclerosis (Fig 4). Thus, when the vasodilating
effects of acetylcholine are blunted, no further increase in the
vasoconstrictor response to acetylcholine is observed with increasing
local atherosclerotic plaque load. These findings indicate that an
increasing extent of atherosclerosis does not lead to
an increased vasoconstrictor response to acetylcholine, as proposed by
studies quantifying vasoconstriction by luminal area
changes.5 7 29 The effect of acetylcholine on luminal
changes observed in these previous studies must have been affected
substantially by the geometric magnification caused by the local
atherosclerotic plaque load. Thus, for coronary segments
exceeding a certain amount of atherosclerotic plaque load, there is no
evidence for the presence of hyperreactivity to acetylcholine with
further increasing atherosclerotic plaque load.
Study Limitations
In the present study, the extent of
atherosclerosis did not exceed 30% luminal narrowing
as determined by angiography. In addition, extremely fibrous or
calcified coronary segments were excluded from analysis
because of the difficulties in determining the arterial
dimensions by ultrasound. Thus, we cannot comment on the effects of
atherosclerosis on coronary vasomotor tone in
advanced coronary artery disease with the presence of
hemodynamically significant stenoses. Moreover,
calculation of the geometric model idealizes the coronary
dimensions to concentric circles. However, besides the fact that
segments with a small amount of wall thickening were mainly concentric,
there was no significant difference in vasoreactivity and vasomotor
tone between segments with eccentric and concentric wall thickening. We
did not assess dose-response effects of
nitroglycerin. Thus, we cannot comment on whether
atherosclerotic vessel segments exhibited an altered sensitivity to
nitroglycerin in addition to the observed reduced
reactivity. Finally, although experimental studies put forward the
hypothesis that local generation of nitric oxide by the
endothelium might contribute to vascular
remodeling,2 this hypothesis could not be tested in our
patients because infusion of an inhibitor of basal nitric
oxide synthesis into the coronary circulation of patients with
coronary atherosclerosis might expose
those patients to a potentially hazardous risk. However, Lefroy et
al30 recently reported data on the effects of the nitric
oxide synthesis inhibitor
NG-monomethyl-L-arginine
(L-NMMA) on epicardial artery vasoreactivity in patients with normal
coronary arteries and without risk factors for coronary
atherosclerosis. Importantly, they observed a
significant inverse correlation between the magnitude of the
vasoconstrictor response to L-NMMA and the vasodilator response to
sodium nitroprusside. Thus, segments with a large response to L-NMMA
had only a small incremental response to sodium nitroprusside,
suggesting a high basal nitric oxide activity associated with reduced
baseline tone. Although these data are not completely transferable to
our patient population, they clearly demonstrate not only that a
decrease in baseline vasomotor tone contributes to the reduced
vasodilator capacity in response to nitrates but also that an increased
basal nitric oxide activity constitutes a potential mechanism of
functional remodeling.
Clinical Implications
Previous studies demonstrated an augmented constrictor response to
acetylcholine in proximal compared with distal epicardial artery
segments,31 suggesting a different reactivity of proximal
and distal coronary artery segments. Moreover, coronary
arterial segments at branching points were shown to
demonstrate increased constrictor responses to
acetylcholine.32 It is well known that atherosclerotic
wall thickening is most pronounced in proximal coronary artery
segments33 and at branching points.34 The
results of the present study suggest that the increased constrictor
responses at these sites merely reflect the effects of geometric
magnification rather than an altered vascular reactivity in these
segments. Assessment of absolute vasomotor tone as proposed in the
present study provides the potential to investigate
coronary artery responses in terms of hyperreactivity and, in
dose-response curves, hypersensitivity to vasoactive stimuli and
should therefore enable the differentiation of true hyperreactivity
from physiological responses magnified by local
atherosclerotic plaque load.35 In addition, quantification
of basal vasomotor tone as a measure of functional remodeling of
atherosclerotic coronary arteries provides the basis for
assessing the effects of risk factors for coronary artery
disease on the process of vascular remodeling.
In summary, quantitative assessment of epicardial artery vasomotor tone in vivo by combining ultrasound and angiographic measurements demonstrates that atherosclerosis is associated with an impairment in the vasodilator response to nitroglycerin. In addition, basal vasomotor tone decreases with increasing atherosclerotic plaque load, suggesting the presence of a functional remodeling process in atherosclerotic coronary arterial segments, which appears to be a primary determinant of the response to vasoactive stimuli.
Available Data
Luminal area change from baseline to
nitroglycerin is determined by angiography. The factor
of luminal area change (l) is calculated as follows:
 | (1) |
Luminal area (LNTG) and arterial area (ANTG) are measured with ultrasound.
Prerequisites
Wall area is constant:
 | (2) |
The general wall area calculation is as follows:
 | (3) |
Baseline lumen calculation (based on lumen measurement with ultrasound [LNTG] and luminal area changes determined by angiography [l]) is as follows:
 | (4) |
Nitroglycerin-Induced Vasodilator Capacity
The following shows the calculation of the change of
arterial area from baseline to
nitroglycerin. The factor of arterial area
change (a) is determined as follows:
 | (5) |
Incorporating Equation 3 into Equation 5 gives
 | (6) |
Incorporating Equations 2 and 4 into Equation 6 yields
 | (7) |
The change of outer area is given as
 | (8) |
and the change of outer circumference (c) from Equation 8 is
 | (9) |
The percent change of outer circumference from baseline to
nitroglycerin is given by substituting Equation 7 into
Equation 9:
 | (10) |
Total Vasomotor Range
Arterial area change from
nitroglycerin to occlusion is given as
 | (11) |
Total occlusion is
 | (12) |
Incorporating Equations 12 and 2 into Equation 11 gives
 | (13) |
Percent reduction of outer circumference from nitroglycerin to maximal constriction (occlusion), according to Equations 11 and 12, is
 | (14) |
Vasomotor Tone
Percent change of outer circumference from baseline to maximal
dilation with nitroglycerin, according to Equations 5 through 10, is
 |
 | (15) |
Vasomotor tone (in percent) is calculated as follows:
 |
 | (16) |
In the above equations, bas is baseline, NTG is nitroglycerin, and occ is occlusion.
Received January 25, 1995; revision received March 15, 1995; accepted May 22, 1995.
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