Quantitative Assessment of Coronary Vasoreactivity in Humans In Vivo
Importance of Baseline Vasomotor Tone in Atherosclerosis
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.
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.
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.
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).
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.
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 β-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 512×512×8-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.
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.
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]).
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.
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.
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.
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.
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.
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.
Luminal area change from baseline to nitroglycerin is determined by angiography. The factor of luminal area change (l) is calculated as follows:
Luminal area (LNTG) and arterial area (ANTG) are measured with ultrasound.
Wall area is constant:
The general wall area calculation is as follows:
Baseline lumen calculation (based on lumen measurement with ultrasound [LNTG] and luminal area changes determined by angiography [l]) is as follows:
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:
The change of outer area is given as
Total Vasomotor Range
Arterial area change from nitroglycerin to occlusion is given as
Total occlusion is
Percent reduction of outer circumference from nitroglycerin to maximal constriction (occlusion), according to Equations 11 and 12, is
- Received January 25, 1995.
- Revision received March 15, 1995.
- Accepted May 22, 1995.
- Copyright © 1995 by American Heart Association
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