Internal Elastic Lamina Area Research Articles

Abstract 3444: The Effect of Alpha Lipoic Acid on Porcine Coronary Stent Restenosis

Objective: We evaluated the ability of alpha lipoic acid (ALA) to affect on coronary instent restenosis (ISR) in a porcine model. Methods: In vitro experiment: We stimulated porcine VSMC using G-CSF in the presence or absence of ALA. Activation of Akt, vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT)-3 were determined using western blot. And also, cell proliferation and migration assay were determined. In vivo experiment:Balloon overdilation injuries were performed in 2 coronary arteries in 12 pigs. Four weeks after the balloon overdilation injury, 24 bare metal stents were placed for 24 injured coronary arteries. We randomized into two groups (12 stents per group; control group: aspirin and clopidogrel only, ALA group: aspirin and clopidogrel plus 100 mg/kg ALA during 4 weeks). 16 bare metal stents were implanted randomized two coronary arteries in 8 pigs. Group I was control stent group (n=8), Group II was ALA coated stent group (n=8). Follow-up coronary angiogram (CAG) and histopathologic assessment were performed at 4 weeks after stenting. Results: G-CSF increased the phosphorylation of ERK and STAT-3, but after pretreatment of ALA, the phosphorylation of ERK and STAT-3 were significantly reduced. On histopathologic analysis, injury score, internal elastic lamina(IEL) area did not differ significantly between the two groups. The neointimal area was 7.3±0.9 mm2 in control group and 2.2±1.1 mm2 in ALA group (p<0.001), and the histopathologic area of stenosis(AS) was 75.9±8.5 % in control group, 23.5±10.5 % in ALA group (p<0.001). The injury score and IEL area were not significantly different between the two groups. The neointimal area was 7.4±1.1 mm2 in control group and 1.4±0.8 mm2 in ALA group (p<0.001), and the AS was 77.6±10.9 % in control group, 15.6±7.6 % in ALA group (p<0.001). The number of inflammatory cells within neointima was lower in ALA group (63.2±23.7 % vs. 17.6±11.6 %, p<0.001). Conclusion: ALA inhibits the activation of ERK, STAT-3 and proliferation of VSMC. Both high dose of oral ALA and ALA coated stents inhibit neointimal hyperplasia in a porcine ISR model

The Effect of Oral Administration of Alpha Lipoic Acid and Alpha Lipoic Acid Coated Stent in Porcine In-Stent Restenosis Model

Background and Objectives:Alpha lipoic acid (ALA) is beneficial for improving endothelial dysfunction and preventing atherosclerosis-related diseases. We evaluated the affect of ALA on stent restenosis in a porcine model. Materials and Methods:The First experiment: Balloon overdilation injuries were performed in two coronary arteries in 12 pigs. Four weeks after the balloon overdilation injury, 24 bare metal stents were placed for 24 injured coronary arteries. We randomized into two groups (12 stents per group; control group: aspirin and clopidogrel only, ALA group: aspirin and clopidogrel plus 100 mg/kg ALA during 4 weeks). The Second experiment: Stents were randomly implanted in 2 coronary arteries in 8 pigs. Group I was the control stent group (n=8), and group II was the ALA coated stent group (n=8). Follow-up coronary angiogram and histopathologic assessment were performed at 4 weeks after stenting in both experiments. Results:The First experiment On histopathologic analysis, the injury score and internal elastic lamina area did not differ significantly between the two groups. The neointimal area was 7.3±0.9 mm in the control group and 2.2±1.1 mm in the ALA group (p<0.001), and the histopathologic area of stenosis was 75.9±8.5% in the control group and 23.5±10.5% in the ALA group (p<0.001). The Second experiment: The injury score and internal elastic lamina area were not significantly different between the two groups. The neointimal area was 7.4±1.1 mm in the control group and 1.4±0.8 mm in the ALA group (p<0.001), and the histopathologic area of stenosis was 77.6±10.9% in the control group and 15.6±7.6% in the ALA group (p<0.001). Conclusion:Both a high dose of oral ALA and ALA coated stents inhibited neointimal hyperplasia in this porcine coronary artery stent restenosis model. (Korean Circulation J 2006;36:495-502)

Effects of beta-radiation using a holmium-166 coated balloon on neointimal hyperplasia in a porcine coronary stent restenosis model.

Brachytherapy is a promising method of preventing and treating coronary stent restenosis. The present study was designed to observe the therapeutic effects of a radioactive balloon loaded with Holmium-166 ((166)Ho) in a porcine coronary stent restenosis model. A radioisotope of (166)Ho was coated onto the balloon surface using polyurethane (20 Gy at 0.5 mm depth). Stent overdilation injuries were induced in 2 coronary arteries in each pig (n=8). Four weeks after the injury, control balloon dilation was performed in one coronary artery (Group I) and radiation therapy using the (166)Ho coated balloon in the other coronary artery (Group II) in each pig. Follow-up coronary angiography and histopathologic assessment were performed at 4 weeks after the radiation therapy or the control balloon dilations. With regard to complete blood cell counts, liver function tests, lipid profiles and coagulation tests, there were no differences between the baseline and after radiation. On quantitative coronary angiographic analysis, reference and target artery diameter showed no differences between the 2 groups before, or 4 and 8 weeks after stenting. On histopathologic analysis of groups I and II, the injury score was 1.34+/-0.09 and 1.32+/-0.10, the area of internal elastic lamina was 4.99+/-0.17 mm(2) and 4.82+/-0.20 mm(2), and the luminal area was 3.20+/-0.10 mm(2) and 3.45+/-0.14 mm(2), respectively (p=NS). The neointimal area was 1.78+/-0.11 mm(2) in group I and 1.36+/-0.12 mm(2) in group II (p=0.017), and the histopathologic area of stenosis was 35.1+/-1.6% in group I and 27.6+/-1.9% in group II (p=0.005). In conclusion, beta-radiation of the stented porcine coronary artery using a radioactive (166)Ho coated balloon inhibited stent restenosis without any side effects.

Atherosclerotic enlargement of the human abdominal aorta

Aortic aneurysms usually develop in the atherosclerosis prone infrarenal abdominal aorta. To assess the role of atherosclerosis in aortic enlargement, we studied the relation between plaque formation and aortic size in 30 pressure-fixed male cadaver aortas (age 40–95 years, mean age 67 years). Morphometric analysis of transverse sections of the mid-thoracic and the mid-abdominal aortas included measurement of intimal plaque area, lumen area, plaque and media thicknesses. The area encompassed by the internal elastic lamina area (IEL area) was taken to be an index of aortic size. IEL area increased with age at both the thoracic ( r=0.77, P<0.01) and abdominal ( r=0.54, P<0.01) aortic levels. The aorta also enlarged with increasing plaque area at the thoracic ( r=0.73, P<0.01) and abdominal ( r=0.79, P<0.01) levels. Regression analysis of IEL area on age, body weight, height and plaque area revealed that the primary predictor of thoracic aortic size was age, whereas the primary predictor of abdominal aortic size was plaque area. Plaque thickness in the abdominal aorta was greater than in the thoracic aorta ( P<0.01). Increased plaque area was associated with a significant decrease in media thickness in the abdominal aorta ( r=−0.75, P<0.01) but not in the thoracic aorta. Aortas with relatively enlarged abdominal segments, i.e. those with a thoracic to abdominal ratio of <1.2 ( n=13), were compared to those with a normal ratio (≥1.2, n=17). Relatively large abdominal aortas had twofold greater plaque area ( P<0.001), reduced medial thickness ( P<0.05), fewer medial elastic lamellae ( P<0.01) and greater mural tensile stress ( P<0.05) than relatively normal abdominal aortas. We conclude that plaque formation in the infrarenal abdominal aorta in humans is associated with aortic enlargement and decreased media thickness. These changes may be predisposing factors for the preferential development of subsequent aneurysmal dilation in the abdominal aorta.

Histopathology of postpercutaneous transluminal coronary angioplasty remodeling in human coronary arteries

Background We studied the histomorphometric correlates of long-term successful coronary balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]). Restenosis after PTCA may occur secondary to the failure of compensatory arterial enlargement or post-PTCA arterial constriction. The histopathology of this process in human subjects remains poorly defined. Methods Forty-two coronary segments from 41 patients treated with PTCA 60 ± 58 weeks before death were studied. The histomorphometric findings at the PTCA site were compared with those obtained at a proximal reference site. Results Histologic long-term success was seen in 18 (43%) of 42 arteries. Histologically successful PTCA arteries (PTCA site lumen of ≥50% of the reference lumen) demonstrated a larger acute lumen, smaller plaque size (normalized to the internal elastic lamina area), and thinner adventitia compared with histologic failures. Relative to the reference sites, histologically successful PTCA showed expansion of the external elastic lamina. In contrast, histologic failures showed a reduced external elastic lamina area, suggesting constrictive remodeling. Neointimal area correlated with the extent of internal elastic lamina disruption, but neither variable was related to histologic PTCA success or failure. Conclusions These data provide histomorphometric confirmation of the hypothesis that constrictive remodeling, not neointimal formation, determines the long-term outcome of PTCA. (Am Heart J 1999;138:681-7.)

Coronary artery restenosis after atherectomy is primarily due to negative remodeling

The primary cause of restenosis following directional coronary atherectomy (DCA) remains obscure. “Negative remodeling,” a decrease in vessel area, is believed to be more causative than is increase in plaque area. The DCA technique used in these patients, designed to facilitate the removal of plaque, should allow a more precise evaluation of the relative roles of these two mechanisms. Twenty-five patients underwent DCA. In 17, complete angiographic and intravascular ultrasound (IVUS) images were obtained before and after DCA and at follow-up (6 to 9 months). Internal elastic lamina (IEL), lumen, and plaque areas were calculated at preatherectomy, postatherectomy, and follow-up. Postatherectomy, the mean IEL area increased by 32% and the mean plaque area decreased by 51%, resulting in a significant mean increase in lumen area, 500%. At follow-up when compared to postatherectomy, the change in IEL area was variable; however, the mean did not change significantly (p = 0.58). Plaque area change, when standardized for initial vessel size, was small (mean increase 2.8 ± 3.5%). The mean lumen area did not decrease significantly at follow-up (p = 0.43). A highly significant correlation (r = 0.96) was noted between IEL area change and lumen area at follow-up. In contrast, the correlation between plaque area change and lumen area change over the same period was much less significant (r = 0.64). These data indicate that decrease in IEL area primarily is responsible for restenosis.

Role of nitric oxide in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling

OBJECTIVESThe purpose of this study was to assess the effects of L-arginine and NG-nitro-L-arginine methyl ester (L-NAME) on neointimal hyperplasia and vascular remodeling after balloon angioplasty in the hypercholesterolemic rabbit.BACKGROUNDRestenosis after balloon angioplasty is a consequence of both neointimal hyperplasia and vessel remodeling. Nitric oxide inhibits neointimal hyperplasia, but its effect on vessel remodeling is unknown.METHODSSix weeks after induction of bilateral iliac atherosclerosis, 48 rabbits underwent successful angioplasty in 75 vessels. Eight rabbits (acute group) were sacrificed immediately after angioplasty. The remaining animals received either placebo (chronic control group), or a diet supplemented with either L-arginine (1.5 g/kg/day), or L-NAME (15 mg/kg/day) for 4 weeks after angioplasty.RESULTSThe intimal area was significantly greater in the chronic control group compared to the acute group (2.60 ± 1.03 mm2vs. 1.35 ± 0.62 mm2). This increase in intimal area was lower in the L-arginine group (1.79 ± 0.61 mm2), and greater in the L-NAME group (3.23 ± 0.92 mm2). The area circumscribed by the internal elastic lamina (IEL) increased significantly in the control group compared to the acute group (from 2.52 ± 0.66 to 3.33 ± 0.85 mm2); a more marked increase occurred in the L-NAME group (3.90 ± 0.85 mm2). By contrast, IEL area was unchanged in the L-arginine group (2.41 ± 0.62 mm2). As a result, there was no significant difference in lumen area after 4 weeks in the chronic groups (control: 0.74 ± 0.38 mm2; L-arginine: 0.50 ± 0.43 mm2; L-NAME: 0.48 ± 0.42 mm2).CONCLUSIONSOur results demonstrate that L-arginine inhibits whereas L-NAME stimulates neointimal hyperplasia after experimental balloon angioplasty in the hypercholesterolemic rabbit. However, the lack of vessel enlargement in the L-arginine group resulted in a similar final lumen size in the L-NAME and L-arginine groups.

Inhibition of Chronic Vessel Wall Intimal Hyperplasia Following Acute Anticoagulant Treatment: Relative Effects of Heparin and Dermatan Sulphate

Surface-bound thrombin which contributes to vessel wall hyperplasia, is resistant to inhibition by heparin/antithrombin III (/ATIII) but not to inhibition by dermatan sulphate/heparin cofactor II (/HCII). To determine the effects of heparin and dermatan sulphate on vessel wall hyperplasia after a first or second injury, rabbit carotid arteries first were injured, using a standard procedure (first injury). Half of the first-injury rabbits were given heparin, dermatan sulphate, or saline, 5 minutes before and at 30-minute intervals over 2 hours post-injury, and then allowed to recover. Four weeks later, the first-injury treated animals were killed and their injured carotid arteries were processed histologically. The remaining untreated first-injury rabbits were also allowed to recover. At 4 weeks, those rabbits were re-anesthetized and their first-injury arteries (which were occluded >75%), were isolated, and vessel wall lumen patency was re-established by endarterectomy (second injury). During this second injury, the animals were treated with heparin, dermatan sulphate, or saline as described above. Four weeks after this second injury, these rabbits were killed and their second injury arteries were processed histologically. Intimal hyperplasia determined histologically, was expressed as an x-fold increase in vessel wall cross-sectional area (i.e., [(media+intima area)÷media area]). Vessel wall lumen occlusion was expressed as [1−(lumen area÷internal elastic lamina area)×100; % occlusion]. Vessel wall area in the saline-treated animals, increased 2.6±1.2 and 2.4±1.0 fold respectively, means±SD, n=12, within 4 weeks of the first and second injuries. These increases were due to intimal hyperplasia and associated with 75±19% and 79±21% occlusion of the vessel wall lumen, respectively. Heparin had little effect, whereas dermatan sulphate (1) decreased hyperplasia by 45% after the first injury and by 47% after the second injury, p<0.008 and <0.03, respectively, and (2) decreased vessel wall occlusion 47±12% and 33±5% after the first and second injury, respectively. We conclude that (1) dermatan sulphate/HCII may be a useful inhibitor of vessel wall hyperplasia following vessel wall injury, and (2) this effect can be achieved by an acute anticoagulant treatment at the time of injury, unlike heparin/ATIII.

Experimental hypercholesterolemia induces ultrastructural changes in the internal elastic lamina of porcine coronary arteries

The internal elastic lamina (IEL) serves as a barrier for cells and macromolecules migration between the intima and the media in the vascular wall. Several investigators have reported internal elastic lamina ultrastructural changes in elastic arteries with atherosclerosis. However, no quantitative and qualitative assessment of the internal elastic lamina architecture in muscular arteries such as the coronary circulation during early atherosclerosis have been performed yet. In this study, we therefore evaluated the ultrastructural morphological changes of the IEL in the coronary circulation of pigs fed with high cholesterol diet. Animals were sacrificed after being fed either a high cholesterol diet for 10–12 weeks ( n=5, 12 coronary segments) or a control diet ( n=4, 15 coronary segments). Coronary arteries were analyzed by transmission and scanning electron microscopy. In addition, computerized digital analysis of the images obtained by confocal scanning microscopy was performed for the quantitation of the morphologic changes in the internal elastic lamina. Confocal microscopy and scanning electron microscopy revealed an altered pattern characterized by large oval fenestration formation in the internal elastic lamina of hypercholesterolemic animals. Computerized morphometric analysis of confocal microscopy images demonstrated that compared to controls, the IEL of cholesterol-fed animals was characterized by an increase in the minor diameter of the fenestrae (2.16±0.04 μm versus 3.32±0.06 μm, P=0.003) and a decrease in the fenestrae density (22 333±1334/mm 2 versus 17 552±931/mm 2, P=0.015) of the internal elastic lamina. The percentage of the IEL area covered by the fenestrae correlated with the intimal thickness ( r=0.79, P=0.004). This study demonstrates that experimental hypercholesterolemia is characterized by ultrastructural changes of the internal elastic lamina in the coronary circulation. This study suggests that the IEL may play an important role in the development of structural changes which characterize the early phase of coronary atherosclerosis.

LDL Hypercholesterolemia Is Associated With Accumulation of Oxidized LDL, Atherosclerotic Plaque Growth, and Compensatory Vessel Enlargement in Coronary Arteries of Miniature Pigs

The association between accumulation of oxidized low density lipoprotein (LDL) and (1) progression of atherosclerotic plaques and (2) compensatory enlargement was assessed in the coronary arteries of LDL-hypercholesterolemic miniature pigs. In miniature pigs fed a 4% cholesterol diet, LDL cholesterol levels increased from 27+/-3.5 mg/dL (mean+/-SEM, n=36) to 250+/-28 mg/dL (n=10), 260+/-15 mg/dL (n=6), and 260+/-17 mg/dL (n=10) at 6, 14, and 24 weeks, respectively. Mean intimal areas of lesions in the left anterior descending coronary artery of hypercholesterolemic pigs were 0.16+/-0.046 mm2 at 6 weeks (n=10) and increased 5.4-fold (n=6, P<.05) and 10.6-fold (n=10, P<.001) at 14 and 24 weeks, respectively. Plaque growth was associated with an increase in mean internal elastic lamina area, from 1.44+/-0.17 to 4.38+/-0.52 mm2 (P=.007) and in mean luminal area from 1.42+/-0.15 mm2 in control pigs to 4.38+/-0.52 mm2 in pigs fed a cholesterol diet for 24 weeks (P=.007 vs control). Levels of total LDL in the intima, measured immunocytochemically, were 0.031+/-0.0098, 0.11+/-0.057 (P< or =.05), and 0.43+/-0.082 U (P<.001) at 6, 14, and 24 weeks, respectively. Corresponding levels of oxidized LDL were 0.034+/-0.023, 0.11+/-0.050 (P<.05), and 0.44+/-0.065 U (P<.001), respectively, suggesting that virtually all LDL in the intima is oxidized. Levels of oxidized LDL in the lesions were correlated with the intimal areas (r=.85, P<.0001) but were independent of plasma levels of LDL cholesterol and of oxidized LDL. Plaque levels of oxidized LDL were also correlated with internal elastic lamina areas (r=.72, P<.0001) and with luminal areas (r=.50, P=.0098). Plaque growth in the coronary arteries of LDL-hypercholesterolemic miniature pigs is associated with (1) an increase in plaque levels of oxidized LDL at constant plasma levels of LDL cholesterol and of oxidized LDL and (2) compensatory vessel enlargement proportional to plaque levels of oxidized LDL.

Multiple Arterial Injuries and Prolonged Cholesterol Feeding Do Not Increase Percent Lumen Stenosis: Impact of Compensatory Enlargement in the Microswine Model

While the swine model is frequently utilized in the study of arterial intervention, it has been difficult to create severe peripheral arterial stenosis without total thrombotic occlusion with a single arterial injury and short-term cholesterol feeding. The combination of multiple arterial injuries and prolonged cholesterol feeding was explored in an effort to create lesions with significant luminal compromise. Nineteen microswine were divided into two groups and fed a high cholesterol diet followed by multiple balloon injuries of the iliac arteries. We conclude that repeated balloon injuries and longer cholesterol feeding significantly increase areas of plaque and necrotic core but do not increase percent stenosis because of arterial compensatory enlargement. The microswine iliac arteries enlarge in relation to plaque area and repeated balloon injuries. The compensatory lumen enlargement may be one of the factors resulting in significant angiographic underestimation of plaque area during the early stage of the atherosclerotic disease, but it may functionally delay important lumen stenosis until the lesion occupies 40% of the internal elastic lamina area. This study suggests that repeated injury and longer cholesterol feeding to increase percent stenosis may not be cost effective in this model. However, this model is good for studying an increase in plaque accumulation.

Ultrastructural changes of the internal elastic lamina in experimental hypercholesterolemic porcine coronary arteries

The internal elastic lamina (IEL) serves as a barrier for cells and macromolecules between the intima and media in the vascular wall. We evaluated the morphological changes and quantitative assessments of the IEL architecture in the coronary circulation of pigs fed with a high cholesterol diet. Transmission electron microscopy (TEM) analysis of the IEL from hypercholesterolemic coronary arteries revealed fragmentation of the IEL associated with a decrease in the thickness. Confocal microscopy and scanning electron microscopy (SEM) revealed an altered pattern characterized by a large oval fenestration in the IEL of hypercholesterolemic vessels. Morphometric analysis of confocal microscopy images demonstrated that the IEL of cholesterol-fed animals were characterized by an increase in the minor diameter of the fenestrae (2.16+/-0.04 microm vs 3.32+/-0.06 microm, p=0.003) and a decrease in the fenestrae density (22,333+/-1,334/mm2 vs 17,552+/-931/mm2, p=0.015) compared to controls. The percentage of the IEL area covered by the fenestrae correlated with the intimal thickness (r=0.79, p=0.004). The immunoreactivity for matrix metalloproteinase-3 (MMP-3) increased in cholesterol-fed coronary arteries, predominantly in the neointima. This study demonstrates experimental hypercholesterolemia induced ultrastructural changes of the IEL in the coronary circulation. The IEL may play an important role in the development of structural changes which characterize the early phase of coronary atherosclerosis.

Structural determinants of lumen narrowing after angioplasty in atherosclerotic nonhuman primates

Purpose: The relationship between lumen narrowing, intimal hyperplasia, and wall remodeling after angioplasty was explored in a nonhuman primate model of atherosclerosis. Methods: Cynomolgus monkeys (n = 37) used in long-term atherosclerosis studies underwent left iliac artery balloon injury. The uninjured right iliac artery served as a reference segment for intraanimal comparisons. One month later iliac arteries were fixed by perfusion (100 mm Hg) and removed for cross-sectional analysis to determine mean values for lumen area (LA), intimal area (IA), internal elastic lamina area (IELA), plaque burden (IA/IELA), and depth of wall injury. Values for each balloon-injured iliac artery were normalized to the contralateral uninjured iliac artery (percent of control), and linear regression analysis was performed comparing LA with IA, with IELA, and with depth of injury. Comparisons were also made between those arteries that remained dilated 1 month after balloon injury (LA ≥ 140%; n = 13) and those that renarrowed (LA ≤ 100%; n = 14). Results: For all 37 animals, LA 1 month after balloon injury correlated well with IELA ( r = 0.72; p < 0.001) but not with IA ( r = 0.10; p = 0.54), suggesting that changes in artery size rather than neointimal mass determined lumen caliber. When comparing arteries that remained dilated (n = 13) with those that renarrowed (n = 14), there were no differences in depth of wall injury (injury depth: 0, no injury; 1, intima; 2, IEL; 3, media; 4, EEL; 2.1 ± 0.3 vs 1.6 ± 0.3; p = 0.12), neointimal accumulation (IA, 507% ± 118% vs. 421% ± 81% of control; p = 0.55), or plaque burden (IA/IELA, 0.39 ± 0.04 vs 0.37 ± 0.06; p = 0.71), respectively. However, wall size defined as IELA was significantly smaller in arteries that renarrowed than in those that remained dilated (IELA, 115% ± 14% vs 230% ± 19% of control; p < 0.001). Conclusions: Restenosis after angioplasty has been attributed to intimal hyperplasia, equating loss of lumen caliber with neointimal mass. The data presented herein suggest that lumen narrowing after arterial wall injury may have little to do with intimal mass per se, but rather that a change in wall caliber or wall narrowing is the cause of restenosis. (J Vasc Surg 1997;26:875-83.)

Remodeling of the atherosclerotic arterial wall: a determinant of luminal narrowing in human coronary arteries.

The type of remodeling of the human femoral artery (enlargement or shrinkage) is related to the percentage luminal stenosis. To assess how local changes in vessel size, together with plaque load, determine luminal narrowing in atherosclerotic human coronary arteries. We obtained 576 segments of 28 coronary arteries from 10 patients who had died from noncardiac causes. The lumen area and area circumscribed by the internal elastic lamina (IEL) area, a measure of local vessel size in each histologic cross-section were measured, and the mean lumen diameter and mean IEL diameter were calculated. To correct for arterial tapering, expected reference diameter values were calculated at the same location using linear regression of all data points along the artery. The IEL diameter and lumen diameter were expressed as percentages of the calculated IEL diameter and lumen diameter at the same location (percentage lumen diameter stenosis and relative IEL diameter, respectively). We found a negative relation between the relative IEL diameter and the percentage lumen diameter stenosis. On average, a narrower than expected lumen diameter was accompanied by a smaller than expected IEL diameter. A larger than expected lumen diameter was accompanied by a larger than expected IEL diameter. This relation was found for the left anterior descending, circumflex, and right coronary arteries (y = -0.60x + 105.33, r = 0.48; y = -0.45x + 100.69, r = 0.84; and y = -0.39x + 101.84, r = 0.61, respectively, all P < 0.05). Local luminal narrowing was correlated with a decrease in vessel size. Local remodeling of the artery is one of the determinants of luminal narrowing in the atherosclerotic human coronary artery.

Impact of Local Atherosclerotic Remodeling on the Calculation of Percent Luminal Narrowing

The choice of the reference site in order to calculate percent luminal narrowing mainly depends on which diagnostic tool is used for examination. In intravascular ultrasound or histology, the local area encompassed by the internal elastic lamina (IEL) area is used as a reference. However, the local IEL area, and thereby the reference value, may have been altered by atherosclerotic remodeling. In the present study we examined the impact of local arterial remodeling on the calculation of luminal narrowing. Forty-five human femoral arteries were analyzed, 32 postmortem and 20 in vivo, by intravascular ultrasound. Cross sections were examined every 0.5 cm over an arterial segment length of 10 to 15 cm. In each cross section we measured the lumen area and the IEL area. Two reference areas were used to calculate percent luminal narrowing: (1) the lumen area in the cross section that contained the least amount of plaque (distant reference); and (2) the local IEL area (local reference). In each cross section, the IEL area was expressed as percent of the IEL area in the cross section that contained the least amount of plaque (relative IEL area). Using the distant reference, we found that less luminal narrowing was observed for cross sections with a relative IEL area >100% (indicating compensatory enlargement) than for those with a relative IEL area <100% (indicating shrinkage), whereas percent luminal narrowing calculated using the local reference hardly differed between cross section with a relative IEL area >100% and <100%. Thus, arterial wall remodeling makes the local IEL area an unreliable reference for calculation of percent luminal narrowing. The calculated percent luminal narrowing using a distant, nondiseased reference site reflects the actual change of the luminal area more accurately.

Arterial remodeling after experimental percutaneous injury is highly dependent on adventitial injury and histopathology

Background: The extent and nature of unfavorable geometric remodeling, especially related to the adventitia, has not been studied previously. The purpose of this study was to examine two methods of experimental arterial injury, characterize the extent of remodeling, and determine if remodeling is injury-specific. Methods: Two methods for producing coronary stenoses in pigs were used: heat injury using thermal balloon angioplasty (resulting in adventitial fibrosis), and copper stent implantation (resulting in intense inflammation). Histomorphometric parameters included changes in neointimal thickness (delta neointima) from uninjured to injured sections, and differences in area circumscribed by the internal and external elastic laminas (delta internal elastic lamina area and delta external elastic lamina area, respectively). Remodeling was calculated for each lesion as the enlargement of the external elastic lamina area or internal elastic lamina area for incremental neointimal thickening, expressed as the slopes delta external elastic lamina area/delta neointima and delta internal elastic lamina area/delta neointima. Results: Remodeling indices for the heat lesions were negative (delta internal elastic lamina area/delta neointima=−0.15, delta external elastic lamina area/delta neointima=−0.64) and indicated little remodeling in contrast to copper stent injury (delta internal elastic lamina area/delta neointima=0.95, delta external elastic lamina area/delta neointima=1.20). Conclusions: Remodeling in fibrotic compared to inflammatory lesions differs markedly, and may explain increased restenosis rates observed in thermal balloon angioplasty in patients. This formulation may be useful to study remodeling and restenosis following other interventional technologies.

Compensatory enlargement of angiographically normal coronary segments in patients with coronary artery disease. In vivo documentation using intravascular ultrasound.

Intravascular ultrasound (IVUS) frequently reveals plaque formation at sites with a normal angiographic appearance. However, whether angiographically normal coronary arteries undergo adaptive expansion in vivo remains uncertain. The authors studied 12 patients (11 men, 1 woman; mean age fifty-three +/- ten years [mean +/- SD]) with focal coronary stenosis. Sixty IVUS images from angiographically normal coronary segments were analyzed (14 left main, 44 left anterior descending, and 2 left circumflex coronary arteries). The mean percent area stenosis was 36 +/- 5% and the circular shape factor of the lumen cross section averaged 0.97 +/- 0.02. Both total arterial area and internal elastic lamina area increased as the plaque area expanded (y = 2.13x + 8.07, r = 0.87, P = 0.0001; y = 2.06x + 4.57, r = 0.87, P = 0.0001, respectively), suggesting that for every 1 mm2 increase in plaque area, the total arterial area increased by approximately 2.13 mm2 and the internal elastic lamina area increased by approximately 2.06 mm2. The lumen area also increased as the plaque area expanded (y = 1.06x + 4.57, r = 0.68, P = 0.0001), suggesting that for every 1 mm2 increase in plaque area, the lumen area increased by approximately 1.06 mm2. The medial area did not correlate with the plaque area (r = 0.15, P = 0.26). Thus, compensatory enlargement precedes development of angiographically, detectable coronary atherosclerosis. Furthermore, in early stages of atherosclerosis, arterial enlargement may overcompensate for plaque area. The reduction of the total medial mass does not appear to contribute to the mechanism of compensatory enlargement.

Effect of age, race, body surface area, heart weight and atherosclerosis on coronary artery dimensions in young males

Compensatory arterial enlargement in response to atherosclerosis has been demonstrated for the left main coronary artery. Only limited data is available on the interaction of patient characteristics and atherosclerosis with coronary artery dimensions. The purpose of the present study was to evaluate the influence of age, race, body habitus, heart weight and atherosclerosis on coronary artery dimensions of young males. Hearts from 137 young men (age 32 ± 8 years; 78 black, 59 white) with unnatural deaths (homicide, suicide, accident, drug overdose) were perfusion-fixed, and histologic sections were obtained from the left main, proximal left anterior descending and left circumflex coronary arteries. Computerized planimetry was performed on Movat stained sections. Multiple regression analysis was used to evaluate the relative contribution of plaque size, age, race, heart weight and body surface area on coronary dimensions and compensatory enlargement in response to atherosclerosis. In the left anterior descending and left main coronary arteries, black race, body surface area and age were independent predictors of increased lumen area. In the left circumflex, age was a predictor of lumen area. Plaque area, black race and body surface area independently predicted increased area enclosed by the internal elastic lamina area. There was compensatory enlargement of internal elastic lamina with increasing plaque size in both races in the three arteries, but the percent luminal stenosis was greater in whites due to smaller artery size. Luminal narrowing did not develop until plaques occupied 30% of internal elastic lamina area. Among a population of young men with non-cardiac deaths, blacks have larger lumen and area enclosed by internal elastic lamina than whites. Age and body surface area are major determinants of lumen areas, and compensatory arterial enlargement was seen in all examined arteries in the present study.

Influence of Blockade at Specific Levels of the Coagulation Cascade on Restenosis in a Rabbit Atherosclerotic Femoral Artery Injury Model

The relation among the coagulation cascade, its individual proteins, and the response to vascular injury is largely undefined. We have evaluated the effect of four probes that block specific levels of coagulation cascade on neointimal hyperplasia in the atherosclerotic rabbit arterial injury model. Focal femoral atherosclerosis was induced by air-desiccation injury and hypercholesterolemic diet in 48 New Zealand White rabbits, followed by balloon angioplasty. Active-site inactivated factor VIIa (DEGR-VIIa), which blocks the binding of factor VIIa to tissue factor, was administered (n = 12 arteries) by intravenous bolus (1 mg/kg) at the time of balloon angioplasty and followed by infusion of 50 micrograms.kg-1.h-1 for 3 days; for the control (n = 13 arteries), 150 U heparin was injected as bolus and followed by infusion of saline at 50 microL.kg-1.min-1. Recombinant tissue factor pathway inhibitor (TFPI), which binds factor Xa and inhibits the tissue factor-factor VIIa complex and factor Xa, was given as a 1 mg/kg bolus followed by 15 micrograms.kg-1.min-1 infusion for 3 days (n = 17 arteries). Recombinant tick anticoagulant peptide (TAP; n = 15 arteries) and hirudin (n = 14 arteries), which block factor Xa and thrombin, respectively, were administered as a 1 mg/kg bolus followed by 5 micrograms.kg-1.min-1 infusion for 3 days. These three groups had their own controls (n = 14 arteries). There were no differences among treatment groups in preangioplasty and postangioplasty minimal luminal diameter (MLD) by angiography. The mean MLD 21 days after balloon angioplasty was significantly different between control and DEGR-VIIa-treated groups (0.74 +/- 0.25 and 1.24 +/- 0.27 mm, respectively; P = .0001) and between the TFPI-treated group and others (0.88 +/- 0.21 mm for control, 0.97 +/- 0.22 mm for hirudin-treated, 0.98 +/- 0.14 mm for TAP-treated, and 1.32 +/- 0.21 mm for TFPI-treated arteries; P = .0001 by ANOVA). By quantitative histological analysis, the ratio of neointimal cross-sectional area compared with the area of internal elastic lamina in the DEGR-VIIa-treated group was significantly less than control (0.48 +/- 0.12 versus 0.67 +/- 0.12, P = .0001), and the ratio of neointimal cross-sectional area to the area demarcated by the internal elastic lamina of the TFPI-treated group was significantly reduced compared with the other groups (0.46 +/- 0.20 for TFPI-treated, 0.67 +/- 0.15 for hirudin-treated, 0.61 +/- 0.15 for TAP-treated, and 0.64 +/- 0.13 for control groups; P = .003). Treatment with DEGR-VIIa or TFPI for 3 days in this rabbit atherosclerotic injury model reduced angiographic restenosis and decreased neointimal hyperplasia compared with controls. These findings highlight the importance of early initiators of the extrinsic coagulation pathway, especially factor VII and tissue factor, in the response to arterial injury.

Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model.

In de novo human atherosclerosis, compensatory vessel enlargement limits the effect of intimal plaque formation on lumen narrowing. We hypothesized that arterial remodeling may also play an important role in determining the chronic lumen size after angioplasty and tested this hypothesis using the hypercholesterolemic rabbit iliac artery angioplasty model. Morphometric analysis of histological cross-sectional areas of vessels from animals killed immediately after angioplasty (acute group, n = 11) were compared with the same areas from animals killed 4 weeks after the procedure (chronic group, n = 37), when restenosis occurs in this model. The area circumscribed by the internal elastic lamina (IEL) increased by 20% from acute to 4 week follow-up after angioplasty (acute group, 2.36 +/- 0.45 mm2, chronic group, 2.84 +/- 0.89 mm2). Over the same time period, intimal area increased by 0.82 mm2. Despite this increase in intimal area, lumen area decreased by only 0.34 mm2 because of the compensatory enlargement of the IEL area. In the chronic group, polynomial regression analysis revealed a quadratic relation between intimal area and lumen area (R2 = .35, P < .001). A lumen area of 0.45 mm2 (the nadir of the quadratic relation) was used to divide the chronic group into two subgroups: restenotic (n = 21; lumen area, < 0.45 mm2) and nonrestenotic (n = 16; lumen area, > 0.45 mm2). By definition, there was a significant difference in lumen area between the two subgroups (0.15 +/- 0.15 mm2 for restenotic; 0.73 +/- 0.18 mm2 for nonrestenotic). Surprisingly, the intimal areas in the two subgroups were virtually identical (2.41 +/- 0.92 mm2 for restenotic, 2.49 +/- 0.69 mm2 for nonrestenotic, P = NS). The difference in the lumen area between restenotic and nonrestenotic vessels was a result of the significantly greater IEL area in the nonrestenotic subgroup (3.22 +/- 0.83 mm2 for nonrestenotic, 2.56 +/- 0.84 mm2 for restenotic, P < .05). In both restenotic and nonrestenotic vessels, the IEL area increased with increases in intimal area. In the restenotic arteries, the slope of this correlation was < 1, showing inadequate compensatory enlargement for the intimal plaque. In the nonrestenotic vessels, the slope was > 1, limiting the effect of intimal plaque on luminal narrowing. These data indicate that the iliac artery in an atherosclerotic rabbit model compensates for intimal formation after angioplasty by vessel enlargement. Furthermore, the degree of vessel enlargement is more important than intimal area in determining the chronic lumen size.