Preserved Vasodilatory Response to Nitroglycerin in Saphenous Vein Bypass Grafts
Background Uncertainty exists regarding the effects of nitroglycerin on atherosclerotic segments of coronary arteries, and information on vasoreactivity of saphenous vein bypass grafts is sparse. Intravascular ultrasound enables identification of atherosclerosis in angiographically normal segments and allows continuous determination of alterations in cross-sectional lumen areas.
Methods and Results Patients with documented coronary atherosclerosis were studied. Vessel morphology and lumen area at baseline and after 100 to 200 μg nitroglycerin were assessed at 10-second intervals for 60 seconds in vessel segments without angiographically apparent lesions. Coronary artery saphenous vein bypass grafts from 11 patients were compared with native coronary arteries in 16 different patients. Atherosclerosis was present in all vessel segments studied. There was a rapid increase in lumen area compared with baseline after intravascular nitroglycerin in both native coronary arteries and saphenous vein bypass grafts. Maximum lumen area dilatation was 19.6±12.2% in saphenous vein bypass grafts and 19.7±13.1% in native coronary arteries. An earlier peak response in saphenous vein bypass grafts (34.5±6.9 seconds) compared with native coronary arteries (44.7±8.5 seconds; P=.003) was found. Vessel wall area remained constant during vasodilation, but there was a significant reduction in measured wall thickness (P=.034).
Conclusions In patients with documented coronary artery disease, intravascular ultrasound reveals substantial atherosclerosis in angiographically normal vessel segments. In these vessel segments, both native coronary arteries and saphenous vein bypass grafts exhibit prompt vasodilation with the intravascular administration of nitroglycerin. The vasodilatory capacity in response to nitroglycerin seems to be preserved in transposed, denervated, and devascularized saphenous veins.
The endothelium-independent smooth muscle relaxant nitroglycerin is routinely used to achieve vasodilation in coronary arteries. However, the multiple mechanisms by which it affects the cardiovascular system are still under investigation. Moreover, little information is available on the effect of nitroglycerin on coronary SVBGs in humans.
Saphenous vein bypass grafting is still the major surgical approach to revascularize multivessel coronary artery disease. Morphological changes in these transposed veins, which are believed to be secondary to the effects on the veins of the high-pressure system, have been described.1 2 3 4 5 Intimal thickening appears 1 month after implantation, increases with time, and includes intimal fibrotic proliferative lesions.1 2 3 4 The effects of vessel wall ischemia caused by the loss of vasa vasorum and denervation of the SVBGs on properties of the vessel wall are unclear.5 6 Besides fibromuscular intimal hyperplasia, it has been reported that medial smooth muscle cells are replaced, completely or in part, by fibrous tissue and collagen; in the adventitia, there is a marked increase in fibrous tissue with severe disruption or complete replacement of elastic fibers.5 All these factors are considered to markedly increase the stiffness of the vein graft and thus have the potential to reduce vasodilatory responsiveness to nitroglycerin. In fact, SVBGs are often thought of as hyperplastic passive conduits; therefore, nitroglycerin is not routinely used to help determine the appropriate size of interventional devices to be used in these vessels.
We therefore used IVUS to examine the quantitative and temporal effects of intracoronary nitroglycerin in a clinical setting and to compare the response to nitroglycerin injection in native coronary arteries and SVBGs.
The study group comprised 27 consecutive patients with stable angina pectoris undergoing diagnostic coronary angiography and IVUS for evaluation of the severity of coronary atherosclerosis. All patients were considered for percutaneous transluminal coronary angioplasty. We studied 16 native coronary arteries and 11 SVBGs. Table 1⇓ gives details on the study groups. In accordance with the clinical practice in our hospital, the patients were maintained on their current medications except for short-acting nitroglycerin. Written informed consent was obtained from each subject. Patients with rest angina or ECG changes during passage of the IVUS catheter or during IVUS imaging were excluded.
The IVUS imaging system consisted of an imaging catheter (Sonicath, Boston Scientific Corp) and a SONOS Intravascular System imaging console (Hewlett-Packard). The imaging catheter has a 30-MHz single piezoelectric crystal transducer mechanically rotating at 1800 rpm within a 3.5F monorail over-the-wire catheter sheath.
The right or left femoral artery was punctured by the Seldinger technique, an 8F or a 9F arterial introducer sheath was advanced retrograde over a guide wire, and the sheath was placed in the femoral artery. After completion of angiography of native coronary arteries and SVBGs, the imaging catheter was introduced through an 8F or a 9F coronary guiding catheter over a 0.014-in guide wire. The imaging catheter was placed in an angiographically normal portion of the vessel distal to the lesion under fluoroscopic guidance. IVUS imaging was performed at baseline and during 60 seconds after an intracoronary bolus dose of 100 to 200 μg nitroglycerin. The protocol favored administration of 200 μg nitroglycerin but allowed 100 or 150 μg in patients with systemic arterial blood pressures of ≤120 mm Hg at the time of administration. The nitroglycerin was administered proximal to the imaging site through the coronary guiding catheter. The two-dimensional images of the vessels were displayed on a SONOS Intravascular System imaging console and recorded on a 0.5-inch super VHS videotape for subsequent playback, review, and quantitative analysis. Vessel areas were determined at baseline and for each 10-second interval. Wall thicknesses and diameters were determined at baseline and at the time of maximum dilation for each vessel. Simultaneous systolic and diastolic blood pressures and ECGs were recorded.
IVUS images were analyzed off-line with a SONOS Intravascular System. Each vessel lumen area was measured by planimetry. To assess the vessel lumen area (in square millimeters), the lumen-intima border was traced, and the area within this border was measured with a planimeter (Fig 1⇓). In SVBGs, the entire vessel CSA was measured by tracing the outer border of the whole vessel. In native coronary arteries, the EEL of the vessel was defined as the outer border of the sonolucent zone, and the area within the EEL (the EEL area) was measured by planimetry. Vessel wall area was calculated as EEL area or CSA minus lumen area. Percent area stenosis was calculated as (vessel wall area/EEL area or CSA area)×100. Maximum and minimum lumen diameters were identified and measured. Wall thicknesses were also measured along the minimum and maximum lumen diameters. For each diameter, the thinner and the thicker portions of the vessel wall were grouped and processed separately. Thus, four samples of vessel wall thickness were collected (Fig 2⇓). Atherosclerosis was considered to be present if the maximal thickness of the intimal leading edge was >0.3 mm, the sonolucent zone thickness was >0.2 mm, or both.7 8 Plaque morphology was considered not to be severely calcified or fibrotic if less echo-dense than the adventitia, according to previously described criteria.7 9
Interobserver variability of lumen diameter and CSA determinations by IVUS was calculated from measurements by two independent observers in 15 randomly selected patients. Intraobserver variation was determined by measurements in the same patients on two occasions separated by a minimum of 1 month. Absolute differences were used in the analysis, and the variability was given as mean percent difference±SD between measurements.
Data are given as mean±SD. Differences from baseline within each group were tested with a repeated measures ANOVA with contrast. Overall vasodilatory response to nitroglycerin was compared in a two-factor repeated measures ANOVA with vessel group as the between-factor and time as the within-factor variable. An unpaired t test for continuous variables or Fisher's exact test for categorical data was used for comparison between groups. A value of P<.05 was considered significant.
The study groups (16 native coronary arteries and 11 SVBGs) were comparable in important clinical variables (Table 1⇑) and baseline hemodynamics. The SVBGs were 10±5 years old (range, 1 to 16 years). All 27 patients had IVUS evidence of atherosclerosis in angiographically normal segments of the vessels. None had severely calcified or major fibrotic plaques at the imaging site. There was no significant difference in the degree of area stenosis in the vessel segment of interest between SVBGs (46%; range, 37% to 56%) and native coronary arteries (52%; range, 37% to 69%).
Table 2⇓ summarizes the baseline values of the measured variables and responses of these variables to intracoronary nitroglycerin. The vessel sizes at baseline defined by the CSA in SVBGs (17.4±4.4 mm2) and by the EEL area in native coronaries (14.7±5.0 mm2; P=NS) were similar. Baseline lumen area was slightly bigger in SVBGs compared with native coronary arteries (9.4±2.6 versus 7.0±2.2 mm2; P=.014). The calculated vessel wall area at baseline was similar between groups (7.9±4.0 versus 8.0±2.5 in native coronary arteries and SVBGs, respectively).
Reproducibility of IVUS Measurements
Mean intraobserver and interobserver variabilities of CSA determinations by planimetry were 2.6±1.9% and 2.4±2.6%, respectively. Mean intraobserver and interobserver variabilities of maximal lumen diameter determinations were 1.7±2.0% and 2.2±1.7%, respectively. Mean intraobserver and interobserver variabilities of minimal lumen diameter determinations were 1.9±1.5% and 1.9±1.6%, respectively.
Vascular Responses to Nitroglycerin
The vasodilatory response to nitroglycerin was rapid (Fig 3⇓), with a significant increase in lumen area after 20 seconds in both native coronary arteries (P=.0012) and SVBGs (P=.0007). Fig 1⇑ shows a typical response from each vessel group. The significant increase in lumen area was maintained throughout the study. However, because the maximum dilatation was reached before 60 seconds in both vessel groups, there was an apparent attenuation of the vasodilatory effect of nitroglycerin toward the end of the observation period.
Fig 3⇑ demonstrates the vasodilatory response curve to nitroglycerin in SVBGs and native coronary arteries. As shown, the maximal augmentation in luminal area occurred earlier in the SVBGs than in the native coronary arteries and began to attenuate as the native coronary arteries reached their maximal response. Mean maximum lumen area dilatation in SVBGs and native coronary arteries was similar (19.6±12.2% and 19.7±13.1%, respectively; Fig 4⇓). As Fig 5⇓ shows, the peak response occurred significantly earlier in SVBGs (34.5±6.9 seconds) than in native coronary arteries (44.7±8.5 seconds; P=.003).
One patient in the SVBG received 150 μg nitroglycerin, as did 2 patients in the native coronary artery group. Another 3 patients in the native coronary artery group received 100 μg nitroglycerin. There was no relationship between dose and vasodilatory response. Furthermore, the 10 SVBG segments and the 11 native coronary artery segments from patients who received 200 μg nitroglycerin exhibited a time difference between maximum responses identical to the complete study groups. In 5 SVBGs >10 years old, the maximum vasodilation was 16±8%, whereas the remaining 6 vein grafts had a maximum vasodilation of 23±15% (nonsignificant with the Mann-Whitney U test).
The CSA and EEL area increased in parallel with the lumen area (Table 2⇑). The calculated vessel wall area remained unchanged in both study groups during the study period. The wall thicknesses along the minimum and maximum vessel diameters decreased at all four measuring sites in both SVBGs and native coronary arteries at the time of maximum vasodilation compared with baseline (Table 2⇑). There were no significant differences in the degree of vessel wall thinning between vessel type or site, but the overall thinning of the vessel wall with vasodilation was significant (P=.034)
Hemodynamic Responses to Nitroglycerin
There were no differences between groups in heart rate at baseline (70±12 and 70±10 bpm in native coronary arteries and SVBGs, respectively). Heart rate increased by 2.5±3.0 (P=.036) and 3.0±3.0 bpm (P=.029) in the respective groups. Systolic arterial blood pressure was 141±24 mm Hg in patients in whom a native coronary artery was examined and 154±12 mm Hg in the SVBG group (P=NS). Systolic arterial blood pressure decreased with nitroglycerin administration by 17±9 mm Hg (P=.002) in the native coronary artery group and by 23±6 mm Hg (P=.0001) in the SVBG group. The differences between groups in baseline blood pressure and the response to nitroglycerin were not statistically significant.
This is the first study to demonstrate equivalent vasodilatory responsiveness to nitroglycerin in transposed, denervated, and devascularized SVBG veins compared with native coronary arteries. By using IVUS to examine the blood vessels, we could confirm that there was a similar degree of atherosclerosis in the two vessel populations studied. The high temporal and spatial resolutions of IVUS allow accurate assessment of the effects of the pharmacological agents while a blood vessel is being imaged. This approach revealed a rapid onset of vasodilation with the intravascular administration of nitroglycerin in both vessel types, with an earlier peak in SVBGs than in native coronary arteries. The maximum area dilatation achieved was almost identical (19.6±12.2% and 19.7±13.1% in SVBGs and native coronary arteries, respectively). Our results also confirm previous reports of substantial atherosclerosis in angiographically normal vessel segments.8 9 10 11
This study was carried out in a clinical setting and was designed to mimic everyday patient care during intracoronary procedures. An advantage with this approach is that information is gathered that may be directly applicable to the clinical procedures currently practiced in many hospitals. The only entrance criterion for the study was that the invasive cardiologist request an IVUS study and approve the withholding of short-acting nitroglycerin during the angiographic study. As Table 1⇑ shows, the resulting vessel populations represented comparable groups in terms of age, sex, and medical treatment. However, the SVBG group had more severe native coronary artery disease as described by the proportion of patients with triple-vessel disease. All subjects demonstrated peak vasodilation within the 60-second study period. Hence, both the descriptive and the comparative objectives of this study could be addressed.
Preserved Vasodilatory Responsiveness in SVBGs
We compared the vasodilatory effect of intracoronary nitroglycerin in a clinical setting between SVBGs and native coronary arteries. The maximum increase in lumen area in this setting was ≈20% in both groups. Preserved vasodilatory response in SVBGs is a somewhat surprising finding in the light of numerous reports on morphological changes in the vessel wall in veins used for coronary bypass. These changes include fibrotic changes with loss of smooth muscle in the media and loss of elastic fibers in the adventitia, which may theoretically diminish vasodilatory responsiveness.1 2 3 4 5 Lack of vasodilatory response in SVBGs after intragraft infusion of isosorbide dinitrate was reported in an angiographic study in which vasodilation in both native coronary arteries and internal mammary artery grafts was observed with the same technique.12 Angiographic studies and IVUS measurements, however, may not be fully comparable because of the vasodilatory effect associated with the angiographic contrast agents. Moreover, the different temporal resolutions of the two techniques may also influence the results in case of a short-lived response. Jett et al13 reported a decrease in SVBG flow and an increase in the internal mammary artery flow with nitroglycerin in a canine model in which the respective graft perfused the same vascular bed. This was interpreted as a reflection of a differential responsiveness to nitroglycerin in SVBGs and native coronary arteries because the drug effects on the associated regional vasculature should be similar. Relationships between determinations of blood flow in a canine model and vasodilation in human coronary vessels and SVBGs are not obvious, and comparisons should be carried out with caution. These divergent effects on flow in this canine model do not seem to correspond to a major difference in the vasodilatory response between native arteries and SVBGs in humans. However, Jett et al,13 using the same experimental design, found that nitroprusside (another endothelium-independent nitric oxide donator) increased flow in the saphenous vein. The reason for this finding is not clear.
Similar vasodilatory responses in SVBGs and native coronary arteries may be a result of diminished responsiveness in the native arteries or preserved responsiveness in the SVBG. Brown et al14 reported a maximum increase in CSA with sublingual nitroglycerin of ≈20% in angiographically normal coronary arteries. In a study of cardiac transplant recipients, nitroglycerin administration induced a mean increase of 24% in coronary CSA,15 and in a recent IVUS study, increases of 31±16% in 14 patients with normal vessels on IVUS and 17±6% in patients with IVUS criteria of atherosclerosis were reported.7 In the referenced reports, great care was taken to stop all vasodilator treatment before the studies. In contrast, we chose a priori to maintain all patients on their medications to assess the true milieu in which patients receive nitroglycerin (ie, while on other vasoactive medication). Similar magnitudes of the increase in CSA in native coronaries in our study despite maintenance of vasodilator treatment favor the interpretation that responsiveness to nitroglycerin is preserved in our SVBG vessel population rather than the view that we are observing a substantial diminution in the responsiveness of the native coronary arteries. Hence, the fibrotic changes that generally occur in old SVBGs do not seem to hinder smooth muscle–mediated vasodilation.
The reasons for a preserved vasodilatory responsiveness in SVBGs are not known. Because nitroglycerin is an endothelium-independent vasodilator, its function may be less affected by the intimal thickening that occurs in SVBGs. Although human in vivo data on endothelial function in SVBGs are lacking, in vitro information suggests attenuation of endothelium-dependent vasodilation coexistent with preserved responsiveness to nitric oxide.16 In a comparative study of coronary vein grafts retrieved during repeated bypass surgery and fresh human saphenous veins, Cross et al17 reported loss of vasodilatory response to the endothelium-dependent acetylcholine in SVBGs but preserved although diminished vasodilatory response to a receptor-independent endothelium-dependent calcium ionophore A23187. These data are compatible with our observation that SVBGs that have intimal changes still exhibit nitroglycerin-induced vasodilation.
Vasoreactivity in Atherosclerotic Native Coronary Arteries
Several studies of coronary artery vasoreactivity in humans have shown increased vasoconstriction in response to acetylcholine, an endothelium-dependent vasodilator in animals, in vessels with demonstrated or suspected atherosclerosis, whereas the vasodilatory response to nitroglycerin has been shown to be preserved.18 19 These results have been interpreted as an indication of selective endothelial dysfunction. Our data confirm the previous observations of maintained vasoreactivity to nitroglycerin also in mildly to moderately atherosclerotic coronary arteries. The coupling between early atherosclerosis and the acetylcholine effect was challenged in a recent IVUS study showing that the epicardial vasomotor response to acetylcholine is not predicted by coronary atherosclerosis as assessed by IVUS.20 Hence, a more specific discussion of the pathophysiological mechanisms determining the vasodilatory capacity in SVBGs and in mildly atherosclerotic coronary arteries is needed in further studies.
Vasodilation as a result of increased distal flow has also been reported.21 This vasodilatory effect is believed to be endothelium dependent, and because there is intact endothelium present in SVBGs, a contribution of flow-mediated vasodilation may influence our results.
Differences in the Patterns of Vasodilation Between SVBGs and Native Coronary Arteries
We found that SVBGs had more pronounced early vasodilation and a significantly shorter time to maximal vasodilation compared with native coronary arteries. In the present study, this finding was very consistent, but the reason is not clear. Both vessel populations showed an apparent attenuation of the vasodilatory effect of nitroglycerin toward the end of the observation period. This effect could be explained to some extent by the 12% to 15% decrease in systolic blood pressure that accompanied the doses of intracoronary nitroglycerin given.
Potential Study Limitations
The fact that patients were not withdrawn from oral vasoactive drugs before the study indicates that our findings could represent only the additional effect of intravenous nitroglycerin with the net pharmacological effect of other oral medications. However, the degree of maximum vasodilation achieved in our study is similar to that reported in several previous reports.7 14 15 Even so, our observation may not be interpreted as a comparison of the total vasodilatory capacity of nitroglycerin in these two vessel populations. The hemodynamic effect, ie, the decrease in blood pressure with the use of nitroglycerin, may also be more pronounced in patients in the upright position and thus may diminish the vasodilatory response to the drug. These limitations are not likely to affect our conclusions because the purpose of this study was to describe effects of nitroglycerin in a clinical setting and the methodology was identical in the two populations studied. An inherent limitation with IVUS is that the effect can be monitored only at one cross-sectional site of a vessel and thus there is no way of knowing whether the vasodilation at the measuring site is influenced by inappropriate vasodilation proximal or distal to the IVUS transducer. The presence of a catheter in the vessel may trigger vasoconstriction, and restriction of the lumen area by the catheter itself may reduce flow. The catheter technique may thus theoretically alter the baseline area determinations and possibly influence the vasodilatory capacity of the vessel segment studied. Hence, factors directly related to the methods applied may restrict comparability between IVUS studies and angiographic studies (vasodilatory effect of the angiographic contrast agents per se and poor temporal resolution). The described method-dependent effects should be accounted for whenever studies are compared or comparative studies are planned.
In summary, regardless of the precise pathophysiological mechanisms affecting vasodilatory capacity, this is the first IVUS study to demonstrate preserved vasodilatory responsiveness to intracoronary nitroglycerin in SVBGs compared with native coronary arteries. The effect of nitroglycerin appeared promptly in both vessel groups. Used in a clinical setting in patients with IVUS-documented atherosclerosis who were treated with oral vasoactive drugs, nitroglycerin seems to yield increases in lumen CSA similar to those found in previous studies on native coronary arteries. These observations indicate that vasoreactivity in the transposed, morphologically changed, and denervated saphenous vein operating in a high-pressure system may play a role in modulating regional myocardial perfusion.
Selected Abbreviations and Acronyms
|EEL||=||external elastic lamina|
|SVBG||=||saphenous vein bypass grafts|
This study was supported by grants from The Wenner-Gren Center Foundation, St Paul's Hospital, South Korea; Japan Self Defense Forces Central Hospital; Lee E. Siegel, MD, Memorial Fund; the Herbert Stein, MD, Research Fund; and the Western Cardiac Research Fund.
- Received May 5, 1996.
- Revision received June 26, 1996.
- Accepted July 8, 1996.
- Copyright © 1996 by American Heart Association
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