Compensatory Enlargement in Coronary and Femoral Arteries Is Related to Neither the Extent of Plaque-Free Vessel Wall Nor Lesion Eccentricity
A Postmortem Study
Abstract Arteries may demonstrate compensatory enlargement in response to plaque accumulation. It has been proposed that enlargement is achieved by the expansion of the nondiseased (plaque-free) vessel wall. In this study, we assessed this hypothesis. Post mortem, 32 atherosclerotic coronary arteries (left anterior descending, n=10; left circumflex, n=11; and right coronary, n=11) and 54 atherosclerotic femoral arteries were pressure fixed. Cross sections (coronary arteries, n=537; femoral arteries, n=1602) were obtained for analysis every 2.5 mm for the coronary arteries and every 5.0 mm for the femoral arteries. From these cross sections, we determined the degree of remodeling and an eccentricity index. Finally, we measured the extent of plaque-free vessel wall. The plaque-free vessel wall was defined as (1) no plaque present or (2) plaque thickness <0.5 mm. A very weak, negative correlation was observed between the degree of remodeling and the extent of the plaque-free vessel wall (coronary arteries: no plaque r2=.13, P<.01; <0.5 mm plaque r2=.15, P<.05; femoral arteries: no plaque r2=.02, P<.01; <0.5 mm plaque r2=0.04, P<.01). The degree of remodeling did not correlate with the eccentricity index (coronary arteries r2=.002, P>.05 and femoral arteries r2=.001, P>.05). Thus, compensatory enlarged segments did not reveal a larger circumference of plaque-free vessel wall compared with segments that failed to enlarge. This study provides no support for the hypothesis that nondiseased vessel-wall expansion is responsible for compensatory enlargement in atherosclerotic arteries.
- Received February 19, 1997.
- Accepted July 3, 1997.
In both the atherosclerotic coronary1 2 and superficial femoral3 4 arteries, compensatory enlargement has been reported to occur in response to plaque accumulation. The mechanisms responsible for arterial wall remodeling in atherosclerosis are unknown, although several mechanisms for compensatory enlargement have been proposed.1 2 3 Enlargement of canine carotid arteries has been shown to occur in response to a long-term increase in blood flow.5 In arterial responses to increased or decreased blood flow, the endothelium plays an essential role.6 However, in patients with coronary atherosclerosis7 8 and in patients with risk factors for coronary artery disease,9 10 11 dysfunction of the endothelium has been demonstrated, which might prevent compensatory enlargement of the vessel. In an atherosclerotic vessel, a focal increase of blood flow velocity may be induced by narrowing of the lumen due to plaque formation. In response to focally increased blood flow velocity and thereby wall shear stress, compensatory enlargement may theoretically be achieved by expansion of the nondiseased part of the arterial wall in an atherosclerotic vessel.1 2 3 When plaque formation reaches the total circumferential involvement of the arterial wall, further enlargement will stop.
Insight into the mechanism of arterial remodeling in de novo atherosclerosis is of particular interest, since recent studies have demonstrated that failure of enlargement or even shrinkage3 12 may seriously enhance arterial luminal narrowing. To study the postulated role of the disease-free part of the atherosclerotic arterial wall in compensatory enlargement, the degree of remodeling was related to the circumferential extent of the nondiseased vessel wall and to lesion eccentricity in both the coronary artery and the superficial femoral artery.
Postmortem, 11 hearts were taken from patients who had not died of cardiac causes (7 men and 4 women; mean age±SD, 78.3±13.8 years), and 54 femoral arteries were taken from 37 donated corpses (17 men and 10 women; mean age±SD, 80.1±8.7 years). Thirty-two coronary arteries and all femoral arteries were fixed by perfusion with formalin 4%, pH 7.4, under pressure. The RCA (n=11), the LAD (n=10), and the LCX (n=11) were dissected from the epicardium over a length of ≈5 to 10 cm from their point of origin. The LAD from 1 patient was not included due to the presence of severe calcifications in the artery. People had donated their bodies by will according to the Dutch Anatomy Act.
To minimize any influence of anatomic tapering of the femoral artery, segments 10 to 15 cm long were selected from 12 cm proximal of the adductor hiatus to 3 cm distal of the adductor hiatus. In this area no major branches originated. Transverse cross sections were obtained every 2.5 mm from the coronary arteries and every 5.0 mm from the femoral arteries, stained with Lawson’s elastic tissue stain, and studied under magnification. The first cross section from a coronary segment was taken 5 mm from the origin. All microscopic images of the cross sections were recorded on VHS videotape with a Sony video camera (3 CCD) for further analysis. A ruler was used for distance calibration.
The cross sections recorded on videotape were analyzed with a digital video analyzer as described previously.13 To determine the degree of remodeling from each cross section, we measured the luminal cross-sectional area, the area encompassed by the IEL. For all coronary and femoral cross sections, we calculated the relative IEL area (ie, degree of remodeling). For the LAD, LCX, and RCA, we calculated the mean IEL area at each location of the corresponding arterial segments. To obtain reference values for the IEL area of cross sections from the coronary arteries (which values were corrected for arterial tapering), we performed a linear regression between the mean IEL area and the distance of the arterial segment. For each coronary cross section, the relative IEL area was calculated by using the IEL area on the corresponding regression line at the same location as the reference value (statistically expected IEL area).
The relative coronary IEL area was calculated as IELarea/IELexpected area×100. In each femoral segment, the cross section that contained the least amount of plaque was chosen as the reference site. Every 5.0 mm, the cross section was compared with this reference site. The relative femoral IEL area was calculated as IELarea/IELarea at reference site×100. A relative IEL area >100% indicates that the arterial segment was enlarged with respect to the corresponding value on the regression line (coronary arteries) or with respect to the reference site (femoral arteries); a relative IEL diameter <100% indicates that the arterial wall was shrunken with respect to the corresponding value on the regression line or with respect to the reference site.
To calculate an eccentricity index, we measured the maximal plaque thickness (Plmax), the minimal plaque thickness (Plmin), the vessel diameter (D1, the vessel diameter at the location of maximal plaque thickness [see Fig 1⇓]) and the vessel diameter perpendicular to vessel diameter D1 (ie, D2) from each cross section. For all coronary and femoral artery cross sections, an eccentricity index ε (Fig 1⇓) was calculated as AC/AB (Equation 1). Substitution of the measured distances D1, Plmax, and Plmin in Equation 1 yields Rearranging Equation 2 results in The eccentricity index gives an estimate of the shift of the center of the lumen from its original position (ie, the center of the cross section). By definition (Equation 3, Fig 1⇓), the eccentricity index will always be ≥1. An eccentricity index of exactly 1 indicates an arterial segment with the center of the lumen in the center of the vessel. An eccentricity index >1 indicates an arterial segment in which the center of the lumen is shifted from the center of the vessel.
To determine the extent of plaque-free vessel wall in each cross section, we quantified the circumferential extent of the plaque-free vessel wall, which was expressed semiquantitatively in hours (12 hours=360°=total circumference; 1 hour=30°). The plaque-free vessel wall was defined in one of two ways: (1) no plaque present or (2) plaque thickness <0.5 mm. The plaque cross-sectional area was calculated by subtracting the luminal area from the IEL area.
All cross sections were categorized into three separate groups as described earlier14 : cross sections with a relative IEL area <95% (shrunken lesions), cross sections with a relative IEL area of 95% to 105% (neither shrunken nor enlarged lesions, ie, unremodeled lesions), and cross sections with a relative IEL area >105% (enlarged lesions).
Data are presented as mean±SD. A linear regression analysis was performed between the relative IEL area and the eccentricity index, as well as between the relative IEL area and the plaque-free vessel wall. Vessel diameters D1 and D2, the extent of the plaque-free vessel wall by both definitions, and the eccentricity index were calculated for each group of lesions. An ANOVA with post hoc a Duncan range test was performed for comparison of all values between the three separate remodeling groups. Differences were considered significant if P<.05.
A total of 538 cross sections from coronary arteries and a total of 1602 cross sections from femoral arteries were examined. The Table⇓ lists the results. In the femoral artery, the extent of the plaque-free vessel wall (<0.5 mm plaque) of the enlarged cross sections was significantly smaller compared with the extent of the plaque-free vessel wall (<0.5 mm plaque) of the unremodeled and shrunken cross sections.
Very weak negative relations between the relative IEL area and extent of the circumference of the plaque-free vessel wall were observed for the coronary arteries (no plaque: r2=.13, P<.01; <0.5 mm plaque: r2=.15, P<.05) and for the femoral arteries (no plaque: r2=.02, P<.01; <0.5 mm plaque: r2=.04, P<.01; Fig 2⇓). Fig 3⇓ shows the absence of any relation between the relative IEL area and the eccentricity index (coronary arteries, r 2=.002, P>.05 and femoral arteries, r2=.001, P>.05).
The mechanism of arterial wall remodeling is unknown. Enlargement of canine carotid arteries has been shown to occur in response to a long-term increase in blood flow.5 In an atherosclerotic vessel, an increase in blood flow is induced by a narrowing of the lumen due to plaque formation. Therefore, it has been proposed that enlargement may be achieved by expansion of the nondiseased part of the arterial wall.1 3 The mechanism of de novo atherosclerotic remodeling has regained interest, since recent studies revealed that the lack of compensatory enlargement and shrinkage are important determinants of luminal narrowing.3 12 In the present study, necropsy material was used to relate the degree of remodeling to the extent of the nondiseased vessel wall and to lesion eccentricity in atherosclerotic coronary and superficial femoral arteries.
If expansion of the nondiseased part of the arterial wall is responsible for compensatory enlargement,1 3 then enlarged lesions are expected be eccentric. In concentric lesions, on the other hand, enlargement is not expected to occur. In the present study, we hypothesized that enlarged lesions would have a larger circumference of nondiseased arterial wall and be more eccentric than nonenlarged or shrunken lesions. The principal findings are that in both the coronary and femoral artery, the relative IEL area did not correlate with the eccentricity index; relative IEL area was correlated very weakly to the extent of plaque-free vessel wall. The correlation, however, is regarded of little interest because the correlation coefficient was close to zero. In addition, the slope of the regression line appeared to be negative, implying that (in contrast to our hypothesis) enlarged segments have a smaller circumference of nondiseased vessel wall than do shrunken segments. Therefore, the present results do not support the hypothesis that expansion of the nondiseased vessel wall is the mechanism of compensatory enlargement in response to plaque accumulation.
Endothelial dysfunction occurs early in the atherosclerotic process.9 11 15 It may be possible that part of the arterial wall histologically appears nondiseased (ie, plaque-free) but has a dysfunctional endothelial layer. The endothelium contributes to the regulation of vascular tone by the release of endothelium-derived vasodilative substances, such as endothelium derived relaxing factor,16 17 18 and endothelium-derived vasoconstrictive substances, such as endothelin.19 20 So it is conceivable that the plaque-free vessel wall did not play any role in arterial wall remodeling because of impaired endothelial function.
Other mechanisms responsible for enlargement may be considered: enlargement of an arterial segment might be achieved by the degrading effect of the developing plaque on the underlying arterial wall.21 In human atherosclerotic lesions, focal overexpression of activated matrix metalloproteinases (ie, a family of enzymes that degrade extracellular matrix)22 may promote weakening of the underlying arterial wall. Induction of enlargement may be a therapeutic strategy. If failed enlargement or even shrinkage is caused by the altered release of vasodilative substances by the dysfunctional endothelium, then drug induced functional recovery of the affected endothelium may restore the capacity of the arterial wall to expand in response to plaque accumulation.
Limitations and Methodological Considerations
The fixation process may alter vessel size, which might explain the observed local differences in relative IEL area. However, we previously3 observed identical relations between the degree of remodeling and the degree of lumen area stenosis in cross sections obtained post mortem and cross sections obtained by in vivo intravascular ultrasound. Therefore, it is unlikely that local shrinkage during fixation fully explains our observations. In addition, by relating a cross section to a reference site from the same arterial segment, interarterial differences due to the fixation procedure can be excluded.
We related the degree of arterial remodeling to the extent of the nondiseased vessel wall and lesion eccentricity at one moment in time. Although the present study does not support the hypothesis that compensatory enlargement is achieved by expansion of the nondiseased vessel wall, we cannot exclude the possibility that expansion of the nondiseased vessel wall was responsible for enlargement. Serial intravascular ultrasound studies are required to test the hypothesis that enlargement is achieved by expansion of the nondiseased wall.1 3 In de novo atherosclerosis, however, the time interval required between observations is too long to be practical.
The extent of the nondiseased part of the vessel wall was quantified by using Lawson’s tissue stain, which provides no information on potential dysfunction of wall layers, in particular the endothelium.9 11 15 Hence, it is conceivable that plaque-free vessel wall in an atherosclerotic vessel should not be classified as nondiseased.
It may be expected that early in the atherosclerotic process, the vessel wall may respond adequately to plaque accumulation by enlargement of the arterial wall. However, the present study does not allow us to draw conclusions regarding the time sequence of both remodeling types: enlargement and shrinkage. To determine whether compensatory enlargement is a phenomenon that occurs early and/or late in the atherosclerotic process, serial intravascular ultrasound studies are necessary.
We considered eccentricity index as a continuous variable; however, it is possible to consider eccentric versus concentric lesions in a dichotomous approach. To categorize all lesions as eccentric or concentric, a cutoff point in the eccentricity index is needed. It may be questionable, however, whether a lesion with an eccentricity index of 1.5 is a concentric or eccentric lesion. From our results, no correlation was found between the degree of remodeling and the eccentricity index. Therefore, no difference in the degree of remodeling between the two artificial categories of concentric and eccentric lesions may be expected. When concentric lesions were defined as those with an eccentricity index <x and eccentric lesions as lesions with an eccentricity index >x, then no significant differences in the relative IEL area between concentric and eccentric lesions were observed for either the coronary (P>.05) or femoral (P>.05) arteries if x≥1.5.
Atherosclerotic arterial wall remodeling was related to neither the extent of the nondiseased part of the vessel wall nor lesion eccentricity. This study provides no support for the hypothesis that expansion of the nondiseased vessel wall is responsible for arterial compensatory enlargement in response to plaque accumulation.
Selected Abbreviations and Acronyms
|IEL||=||internal elastic lamina|
|LAD||=||left anterior descending coronary artery|
|LCX||=||left circumflex artery|
|RCA||=||right coronary artery|
This study was supported by the Dutch Heart Foundation, grant 94-115 (to G.P. and C.B.).
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