Paradoxical Arterial Wall Shrinkage May Contribute to Luminal Narrowing of Human Atherosclerotic Femoral Arteries
Background This study was done to assess how local changes in vessel size, together with plaque load, determine luminal narrowing in atherosclerotic arteries. Fifty-one human femoral arteries were analyzed: 32 postmortem and 19 in vivo by 30-MHz intravascular ultrasound.
Methods and Results Histological and intravascular ultrasound cross sections were examined every 0.5 cm over an arterial segment 10 to 15 cm long. In each cross section we measured the lumen area and the area circumscribed by the internal elastic lamina (the IEL area). In each arterial segment, the cross section that contained the least amount of plaque was the reference site. For each cross section, the lumen area stenosis was expressed as percent of the lumen area in the reference site. Similarly, the IEL area was expressed as percent of the IEL area in the reference site (the relative IEL area). There was a significant negative correlation between the relative IEL area and the lumen area stenosis percentage (r=−.62, P<.001 for histology and r=−.66, P<.001 for intravascular ultrasound). When lumen area stenosis was less than about 25%, mainly compensatory enlargement was observed. When lumen area stenosis exceeded about 25%, however, mainly a decrease of the IEL area was observed, which is consistent with arterial wall shrinkage. Furthermore, the increase in plaque area does not account for the total loss of luminal area. There was a moderate correlation between an increase in plaque area and reduction of the corresponding lumen area (r=.49 and r=.56 for histology and intravascular ultrasound, respectively).
Conclusions The decrease in luminal area cannot be attributed to plaque increase alone. Arterial wall shrinkage is a paradoxical mechanism that may contribute to severe luminal narrowing of the atherosclerotic human femoral artery.
Recent histopathological1 2 3 and intravascular ultrasound4 studies report that coronary arteries tend to undergo compensatory enlargement in response to plaque formation. According to Glagov et al,1 compensatory enlargement is limited, and once the limit has been reached, progressive increase of plaque mass will encroach upon the lumen and lead to luminal narrowing. However, during intravascular ultrasound studies of stenotic femoral arteries we often noticed a reduction of the entire vessel cross sectional area, with relatively little plaque mass at the site of severe stenosis. The aim of the present study was to assess how local changes in vessel size, together with plaque load, determine luminal narrowing in atherosclerotic human femoral arteries.
We report that compensatory enlargement was operative mainly in arteries with less than 25% luminal area obstruction, whereas shrinkage of the entire vessel was present in arteries with more than 25% luminal area obstruction. Shrinkage of the vessel wall may be a major mechanism determining the percentage luminal stenosis in more severely atherosclerotic human femoral arteries.
Thirty-two femoral arteries were taken from donated corpses (13 males, 19 females, aged 80.9±8.6 years [mean±SD]). Four arteries were obtained within 24 hours after death and filled with glycolmethacrylate Technovit 7001 under a physiological pressure of 90 mm Hg and fixed in 4% formalin, pH 7.4. Twenty-eight femoral arteries were taken from corpses that had already been fixed in 4% formalin, pH 7.4. To minimize any influence of anatomic tapering of the artery, segments 10 to 15 cm long were selected from the section of the artery 12 cm proximal to the adductor hiatus to 3 cm distal to the adductor hiatus. In this area no major side branches originated. The femoral arteries were decalcified with 10% EDTA in 5 days and dehydrated in an alcohol sequence ranging from 70% to 100%. From 9 arterial segments embedded in hydroxyethylmethacrylate Technovit 7100, histological cross sections were obtained every 0.5 cm and stained with Verhoeff’s elastic tissue stain. Twenty-three arterial segments were embedded in a mixture of liquified polyethyleneglycol 1000 and polyethyleneglycol 400 in a 4:1 ratio, cut in parts 0.5 cm long, stained with Lawson’s elastic tissue stain, and studied under magnification. All microscopic images of the cross sections were recorded on sVHS videotape with a Sony videocamera (3 CCD) for further image analysis. A ruler was used for distance calibration.
Nineteen patients (11 men and 8 women, aged 58±11 years [mean±SD]) were studied by intravascular ultrasound before routine balloon angioplasty of the superficial femoral artery to treat disabling claudication. Informed consent was obtained from all patients. A 4.2F intravascular ultrasound catheter was used (30 MHz, axial resolution ≤0.1 mm, lateral resolution ≥0.2 mm, bandwidth 60%, penetration depth 10 mm, DuMED). The ultrasound transducer rotated 16 times per second. In contrast to images made by intravascular ultrasound systems with a fixed transducer and a rotating mirror, the DuMED intravascular ultrasound image is not affected by strut artifacts. The resulting images were displayed on a monitor by means of a videoscanned memory and recorded on sVHS videotape.
In all patients a series of cross sectional images was recorded during pull-back of the intravascular ultrasound catheter. To localize the intravascular ultrasound catheter, a ruler was used as a reference during fluoroscopy or a distance transducer was used5 in 14 and 5 patients, respectively. When vasospasm was suspected upon reading of the angiogram, 0.2 mg nitroglycerin was administered through the introducer sheath. When a side branch was found to be present, the image was excluded from further analysis and an image was selected just proximal or distal of the side branch. Ultrasound images were selected every 0.5 cm from a total of 23 arterial segments approximately 10 cm in length. This study therefore concerns 10-cm segments of the superficial femoral artery rather than focal stenoses.
Histological sections and intravascular ultrasound images recorded on videotape were analyzed with a digital video analyzer as described previously.6 We traced the lumen cross sectional area and the area circumscribed by the internal elastic lamina (the IEL area). In the intravascular ultrasound images, the IEL area was traced as the area circumscribed by the interface between the echodense intimal layer and the echolucent media. The plaque cross sectional area was calculated by subtracting the lumen area from the IEL area.
In each arterial segment, the cross section that contained the least amount of plaque was chosen as the reference site. The cross section was compared with this reference site every 0.5 cm. When a long arterial segment (>20 cm) was visualized with intravascular ultrasound, two segments were studied in the same artery to reduce any influence of arterial tapering.
The percentage luminal cross sectional area stenosis was calculated as (1−[lumen area/lumen area of the reference site])×100%. A positive value indicates luminal narrowing or atherosclerotic stenosis and a negative value indicates luminal dilatation or atherosclerotic aneurysm formation. The latter is likely to be due to compensatory enlargement in response to plaque formation.1 Note that this analysis does not allow the assessment of possible lumen enlargement due to plaque regression because in each arterial segment the site with the least amount of plaque was used as the reference (see “Appendix”).
The relative IEL area was calculated as (IEL area of the cross section/IEL area of the reference site)×100%. A relative IEL area of >100% indicates arterial compensatory enlargement, and a relative IEL area of <100% indicates arterial wall, shrinkage with respect to the reference site. For each cross section the increase in plaque area and the increase or decrease of the corresponding lumen area was calculated with respect to the reference site.
All values are presented as mean±SD. A paired Student’s t test was used to determine the difference in IEL area between the most proximal and distal parts of the arterial segments. A third-order polynomial regression analysis was performed between the relative IEL area and the percentage luminal stenosis. Differences were considered significant when P<.05.
A total of 731 histological cross sections and 419 intravascular ultrasound images were examined. Thirty-six histological cross sections were excluded because of cutting artifacts or the presence of side branches. In 41 intravascular ultrasound images it was impossible to differentiate the three different layers within the arterial wall, for instance, because of echo dropout behind calcified lesions. These images were also excluded from further analysis. Of the femoral arteries examined with intravascular ultrasound, 19 segments contained focal stenoses and 4 were obstructed over almost the entire arterial segment.
For 55 arterial segments, 32 examined with histology and 23 with intravascular ultrasound, the lumen area and IEL area were plotted as a function of the length of the segment. The left panels of Fig 1⇓ and Fig 2⇓ illustrate arterial segments obtained postmortem and with intravascular ultrasound, respectively, that demonstrate wall shrinkage, relative to the reference site, at the site of maximal stenosis. Cross sections obtained distal to, at, and proximal to the site of maximal stenosis are shown in Fig 1A⇓, 1B⇓, and 1C⇓, respectively, as well as in Fig 2A⇓, 2B⇓, and 2C⇓. Fig 3⇓ is an example of vessel expansion and luminal overcompensation as well as wall shrinkage in response to plaque formation.
For each arterial segment, the relative IEL area was plotted as a function of the percentage luminal area stenosis. The relation between the degree of arterial wall remodeling, ie, compensatory enlargement or wall shrinkage, and the percentage luminal stenosis is illustrated in the right panels of Figs 1 through 3⇑⇑⇑. In all three examples, wall shrinkage contributed to narrowing of the lumen in the most stenosed parts.
Fig 4⇓ shows the relation between the relative IEL area and percentage luminal stenosis for all arterial segments. This figure demonstrates that the relative IEL area decreased as percentage luminal stenosis increased (histology: r=−.62, P<.001, y=110.89−0.78x+0.012x2 −0.00008x3; intravascular ultrasound: r=−.66, P<.001, y=112.12−0.68x+0.007x2−0.00003x3). If the lumen area stenosis was greater than about 25%, wall shrinkage dominated over compensatory enlargement. For detailed interpretation of Fig 4⇓, see “Appendix.”
In the histological and intravascular ultrasound cross sections, there was a positive correlation between the increase in plaque area and the decrease in lumen area, as shown in Fig 5⇓ (histology: r=.49, P<.01, y=0.68x+0.76; intravascular ultrasound: r=.56, P<.01, y=0.68x+1.8).
The lumen area, IEL area, and plaque area of the reference sites are listed in the Table⇓. A lumen area of about 22 mm2 corresponds to a lumen diameter of approximately 5.3 mm. An IEL area of about 28.5 mm2 is in accordance with the cross sectional area of 27 mm2 in normal femoral arteries.7
The IEL area did not change from the most proximal to the most distal parts of the arterial segment (histology, 27.5±11.1 to 28.8±12.0 mm2; intravascular ultrasound, 30.8±10.8 to 29.9±10.5 mm2; both P>.1). Thus, the results were not due to tapering of the artery.
Compensatory enlargement of the coronary artery in response to plaque formation has previously been demonstrated.1 2 3 4 High-frequency intravascular ultrasound can be used to visualize the three different layers of the arterial wall8 9 10 and may therefore be used to demonstrate arterial remodeling in vivo.4 In this study we used necropsy material as well as intravascular ultrasound images obtained in vivo to assess the determinants of vascular remodeling that contribute to the changes of the luminal area in atherosclerotic femoral arteries. The two subject groups, whose arteries were studied postmortem or by in vivo intravascular ultrasound, differed in age and cardiovascular history. However, the results of the study were similar for both groups.
The principal findings are that (1) the results of this study are in accordance with those of the study by Glagov et al1 because compensatory vessel enlargement and even luminal enlargement were observed in femoral arteries, (2) both compensatory enlargement and arterial wall shrinkage may be observed in one arterial segment, (3) the degree of arterial wall shrinkage was significantly correlated with the percentage luminal area stenosis, and (4) the decrease in luminal area cannot be attributed to plaque increase alone.
Lumen area varied with changes in both plaque and IEL area. However, this observation does not address the underlying mechanisms of these changes.
In coronary arteries, Stiel et al3 found that the degree of compensatory vessel enlargement increased with percentage lumen area stenosis. The present study, in contrast, provides evidence that in the femoral artery the compensatory enlargement is greatest at the lowest relative percent stenoses (the negative percent stenoses).
Limitations of the Study
The definition of the reference site is of crucial importance to the interpretation of the results of this study. Most histological and intravascular ultrasound studies use the IEL area as the reference, considering it to be a measure of what the lumen would be if no atherosclerotic plaque were present.1 2 3 4 Others use the lumen area of a prestenotic arterial site as a reference. Both stenosis calculations disregard the effect of arterial wall remodeling and aneurysm formation (luminal overcompensation). We chose the arterial site that contained the least amount of plaque as a reference site because it is fair to assume that at the site of least plaque, wall remodeling was least and the lumen approximated the original lumen best.
In most arterial segments the reference site contained plaque, but the amount was limited (Table⇑). A reference site with plaque may itself have undergone compensatory dilation, so that the reference IEL area was too large. This would result in a shift of the x axis in Fig 4⇑ downwards and eliminate the notion of shrinkage. In those cases, not arterial wall shrinkage but failure of arterial compensation would have led to enhanced lumen stenosis. The threshold of approximately 25% luminal narrowing as the point at which wall shrinkage dominates over compensatory enlargement is based on the assumption that the reference site did not undergo any compensatory enlargement and may therefore be too low. However, at the location with maximal luminal stenosis, a smaller IEL area was also observed in arterial segments in which the reference site contained no plaque at all (Fig 1⇑). This finding supports true arterial wall shrinkage. Conversely, just as the reference site might have undergone compensatory enlargement, it might also have undergone arterial wall shrinkage. The latter would result in underestimation of the original IEL area, the upward shift of the x axis in Fig 4⇑, and enhanced contribution of arterial wall shrinkage to luminal narrowing.
The results may be partly confounded by the following methodological problems. First, formalin fixation may have caused geometric changes in the vessel cross sections compared with the physiological situation. However, arteries studied with intravascular ultrasound showed the same trends as the pathological specimens. Secondly, local vasoconstriction may have simulated local arterial wall shrinkage in the intravascular ultrasound study. However, when vasoconstriction was suspected upon reading of the angiogram, nitroglycerin was administered. The possibility cannot be excluded that catheter passage may have caused small local changes in lumen area that were not observed angiographically. Third, plaque regression with concommitant decrease of the IEL area may explain our observations. However, the potential influence of local plaque regression cannot be assessed by using this reference (see “Appendix”). The existence of arterial wall shrinkage seen with intravascular ultrasound (Figs 2⇑ and 3⇑) is supported by the following observations. First, the cross sections that showed some degree of arterial wall shrinkage contained more plaque than the reference sites. This implies that the cross sections classified as “shrunken” are more advanced in time in the atherosclerotic process. Second, all stenotic sites observed with intravascular ultrasound were originally diagnosed with Doppler ultrasonography or angiography performed days or weeks before the dilatation procedure was executed. Therefore, it is unlikely that temporary local arterial spasm reduced the IEL area.
The results of this study also demonstrate that for any luminal area size, large variations in the absolute amount of plaque may be present. Therefore, the increase in plaque load relative to the reference site could not account for the total loss of lumen area relative to the reference site (Fig 5⇑). It should be emphasized that arterial remodeling is a complex mechanism that may vary significantly from site to site along the vessel wall, indicating that the influence of the various determinants is local rather than diffuse.
This study was based on observation and therefore we can only hypothesize about the mechanisms responsible for arterial remodeling. Several explanations for compensatory enlargement have been proposed. An increase of blood flow velocity in a stenosis results in an increase in wall shear stress, which may stimulate endothelial cell–dependent vasodilation.11 12 13 14 The variability in vascular remodeling may be attributed to locally impaired endothelial vasodilator function, which would result in the incapability of arterial segments to undergo compensatory enlargement.12 15
Subnormal flow conditions may be responsible for vessel narrowing.16 Lefroy et al17 found that an inhibition of the small basal release of nitric oxide in distal epicardial coronary arteries is responsible for a decrease in basal diameter of the distal left anterior descending coronary artery. Whether arterial wall shrinkage is to be attributed to flow-dependent inhibition of basal nitric oxide release needs to be investigated.
In conclusion, the mechanism of arterial atherosclerotic obstruction proposed by Glagov et al1 needs to be revised for femoral arteries. Compensatory enlargement often occurs, but a decrease of the IEL area is also frequently observed. A decrease in IEL area, with respect to the reference site with the least amount of plaque, is consistent with local shrinkage of the artery. Wall shrinkage is a form of arterial wall remodeling in response to plaque formation that aggravates rather than alleviates the obstruction to flow by the atherosclerotic plaque.
The inferred clinical implications of local arterial wall shrinkage are twofold: (1) Balloon angioplasty of a shrunken atherosclerotic artery with a relatively small amount of plaque may yield different immediate and long-term results than dilation of a compensatory enlarged artery narrowed by a large amount of plaque and (2) because in coronary arteries anti-Glagov remodeling might also be found, local arterial wall shrinkage might contribute to the surprisingly high frequency with which adventitial tissue is found in atherectomy specimens.18 19
A schematic representation of Fig 4⇑ is shown in Fig 6⇓, illustrating the different types of arterial remodeling. Line X represents all cross sections in which only the increase in plaque area caused the luminal stenosis. Line P represents all cross sections in which only arterial wall shrinkage caused the luminal stenosis or, conversely, arterial wall enlargement caused an increase in lumen area (negative percentage stenosis). Line Y represents all cross sections in which an increase in plaque area was entirely compensated for by vessel enlargement so that lumen area was preserved. In all cross sections represented in area I, arterial wall shrinkage and an increase in plaque are responsible for lumen area stenosis. In all cross sections represented in area II, plaque increase is only partially compensated for by vessel enlargement, so lumen area stenosis is present. In all cross sections represented in area III, luminal enlargement is found together with compensatory enlargement of the vessel wall. A subdivision is made in area III because theoretically it is possible to find cross sections in area IIIb in which the reference site shows a small lumen with a large plaque mass. In that case, a small increase in the IEL area would result in a large relative increase in the luminal area. In Fig 4⇑ no data points were found in the area corresponding to IIIb in Fig 6⇓. Data points in area IV would imply that local plaque regression relative to the reference site was present. However, because by definition the reference site in each arterial segment contained the least amount of plaque, area IV contains no data.
Dr Pasterkamp was supported by a grant from the Netherlands Heart Foundation (92,136). The authors thank Prof C.C. Haudenschild, MD, for his critical comments on the manuscript.
- Received June 2, 1994.
- Revision received August 19, 1994.
- Accepted September 7, 1994.
- Copyright © 1995 by American Heart Association
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