Human Femoral Arteries Research Articles

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.

Blood flow velocity waveforms in the middle cerebral, renal and femoral arteries of human fetuses

Objective: To establish normal reference values for blood flow velocity indices in the human fetal middle cerebral, renal and femoral arteries. Methods: In a cross-sectional study, 83 fetuses in uncomplicated pregnancies were examined. The umbilical artery was also studied to obtain the ratio between blood flow indices in the middle cerebral artery and umbilical artery. Results: Pulsatility index (PI) in the middle cerebral artery manifested an increase in the late second trimester and early third trimester, followed by a fall toward term. Time averaged maximum velocity in the middle cerebral artery increased with advancing gestational age, starting at about 27 weeks of gestation. PI in the renal artery did not manifest any change with advancing gestational age. The femoral artery manifested an increasingly pulsatile pattern with advancing gestational age, and reverse flow in early diastole was first noted at 30 gestational weeks. PI values increased in the third trimester of pregnancy. The umbilical artery PI decreased linearly with advancing gestation. The ratio between the middle cerebral artery PI and the umbilical artery PI increased until 29 weeks' gestational age, then decreased slightly until term. Conclusions: The study demonstrated that in the healthy fetus, the physiological development of PI with gestational age varies from one vessel bed to another. For clinical purposes, gestational age-related and apparatus-specific reference curves of waveform indices should be used.

Blood flow velocity waveforms in the middle cerebral, renal and femoral arteries of human fetuses

Objective: To establish normal reference values for blood flow velocity indices in the human fetal middle cerebral, renal and femoral arteries. Methods: In a cross-sectional study, 83 fetuses in uncomplicated pregnancies were examined. The umbilical artery was also studied to obtain the ratio between blood flow indices in the middle cerebral artery and umbilical artery. Results: Pulsatility index (PI) in the middle cerebral artery manifested an increase in the late second trimester and early third trimester, followed by a fall toward term. Time averaged maximum velocity in the middle cerebral artery increased with advancing gestational age, starting at about 27 weeks of gestation. PI in the renal artery did not manifest any change with advancing gestational age. The femoral artery manifested an increasingly pulsatile pattern with advancing gestational age, and reverse flow in early diastole was first noted at 30 gestational weeks. PI values increased in the third trimester of pregnancy. The umbilical artery PI decreased linearly with advancing gestation. The ratio between the middle cerebral artery PI and the umbilical artery PI increased until 29 weeks' gestational age, then decreased slightly until term. Conclusions: The study demonstrated that in the healthy fetus, the physiological development of PI with gestational age varies from one vessel bed to another. For clinical purposes, gestational age-related and apparatus-specific reference curves of waveform indices should be used.

Contribution of inadequate compensatory enlargement to development of human coronary artery stenosis: An in vivo intravascular ultrasound study

Objectives. This intravascular ultrasound study sought to examine to what extent native coronary artery stenosis is accompanied by vessel wall thickening or inadequate compensatory enlargement (relative vessel constriction), or both.Background. In human femoral arteries, inadequate compensatory enlargement is reported to be a paradoxic mechanism for the development of severe arterial lumen narrowing. However, it is unclear in human coronary arteries whether inadequate compensatory enlargement contributes to the development of critical arterial stenosis.Methods. Thirty-five primary coronary artery lesions from 30 patients (19 men, 11 women; mean [±SD] age 65 ± 13 years) were imaged by intravascular ultrasound. The vessel cross-sectional area and lumen area were measured, and the wall area (vessel cross-sectional area minus lumen area) was calculated at the lesion site and at the proximal and distal reference sites. We defined compensatory enlargement to be present when the vessel cross-sectional area at the lesion site was larger than that at the proximal reference site, inadequate compensatory enlargement when the vessel cross-sectional area at the lession site was smaller than that at the distal reference site and intermediate remodelling when the vessel cross-sectional area at the lesion site was intermediate between the two reference sites.Results. Compensatory enlargement was observed in 19 (54%) of 35 lesions, inadequate compensatory enlargement in 9 (25%) of 35 and intermediate remodeling in 7 (20%) of 35. In the inadequate compensatory enlargement group, reduction of the vessel cross-sectional area contributed to 39% of lumen reduction.Conclusions. Compensatory enlargement commonly (54%) occurs at stenotic coronary lesions. However, inadequate compensatory enlargement results in a substantial amount (39%) of the lumen area reduction in 26% of primary coronary artery lesions.

EFFECT OF THE NEW HMG-CoA REDUCTASE INHIBITOR CERIVASTATIN (BAY W 6228) ON MIGRATION, PROLIFERATION AND CHOLESTEROL SYNTHESIS IN ARTERIAL MYOCYTES

The major relation existing between cell growth, migration and cholesterol homeostasis prompted us to investigate the effect of the new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin (BAY W 6228) on these cellular events. The molecule inhibited in a dose-dependent manner the migration and the replication (evaluated as cell number and nuclear incorporation of 3H-thymidine) of rat arterial SMC with IC 50values of 2.7μ Mand 0.5μ M, respectively. Among the tested statins BAY W 6228 resulted to be the most potent inhibitor of cholesterol synthesis and cell proliferation. Conditions producing 80–90% inhibition of cholesterol synthesis correlate with approximately 50% inhibition of cell growth. Similar results were obtained in SMC from human femoral artery. The in vitroinhibition of cell migration and proliferation induced by BAY W 6228 (80% decrease) was completely prevented by the addition of mevalonate and partially prevented (60–80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites— probably through a prenylated protein(s)—in regulating these cellular events. The present results provide evidence that BAY W 6228 interferes, at least in vivo, with smooth muscle cells migration and proliferation, major processes involved in atherogenesis.

Computation of a location shift between two subsequent intravascular ultrasound registrations by cross-correlation analysis of the lumen area functions

For longitudinal studies on atherosclerosis and restenosis after angioplasty by intravascular ultrasound (IVUS), it is essential that repeated studies are performed at exactly the same location along an arterial section. In human femoral arteries, lumen and plaque area functions of two subsequent IVUS pullback maneuvers were compared by cross-correlation analysis. In cross-correlation analysis of two functions with equal abscissa values, the data sets are repetitively correlated after incremental shifts of the two functions along the abscissa. This results in multiple correlation coefficients with a maximum at the relative position where the two functions show the closest match. In group A (12 patients), both pullbacks were performed after angioplasty and in group B (17 patients) one pullback was performed before angioplasty and the second immediately after angioplasty. In group A, cross-correlation showed a shift between lumen area functions of 5 mm in one patient and no shift in the other patients. Maximum correlation coefficients in group A ranged from 0.644 to 0.978. Four patients from group B showed shifts from 2.5 to 35 mm. Maximum coefficients were significantly smaller than in group A: 0.259-0.864 ( p < 0.01). Plaque area functions in group B showed higher correlations (0.468-0.862, p = 0.034) and only two shifts. Cross-correlation of lumen and plaque area functions may be used to compute location shifts between two subsequent IVUS registrations and to correct such shifts.

Remodeling of de novo atherosclerotic lesions in femoral arteries: impact on mechanism of balloon angioplasty

Objectives. Using 30-MHz intravascular ultrasound in the human femoral artery, we related the mode of arterial remodeling to the immediate result and the mechanism of balloon angioplasty.Background. The atherosclerotic femoral artery may undergo three modes of remodeling in response to plaque formation: compensatory enlargement, failure of compensatory enlargement and paradoxic shrinkage.Methods. In 83 patients an ultrasound catheter pullback maneuver was performed before and after balloon angioplasty. For each lesion (n = 121), the cross section with the narrowest lumen was selected for further analysis. For each cross section, the lumen area stenosis was expressed as percent of the lumen area at an adjacent reference site. Similarly, the media-bounded area was expressed as percent of the media-bounded area at the reference site. Cross sections were classified into one of three groups based on percent relative media-bounded area: 1) >105% (group A, compensatory enlargement, n = 24); 2) 95% to 105% (group B, failure of compensatory enlargement, n = 26); and 3) <95% (group C, arterial wall shrinkage, n = 71). The power of the present study was 99.3% to demonstrate a difference in lumen gain of 2.5 mm2among groups.Results. The gain in lumen area induced by balloon angioplasty did not differ significantly among the three groups (group A, 7.0 ± 4.0 mm2[mean ± SD]; group B, 8.6 ± 4.8 mm2; group C, 8.9 ± 4.9 mm2). Stretch of the media-bounded area was observed in all three groups, but it was significantly larger in group C (7.5 ± 5.2 mm2) than in the other two groups (group A, 3.9 ± 5.1 mm2; group B, 5.1 ± 4.1 mm2). A significantly positive correlation between balloon/media-bounded area ratio and elastic recoil was observed for cross sections in groups A and B (r = 0.71 and r = 0.69, respectively). However, no correlation was observed between balloon/media-bounded area ratio and elastic recoil for cross sections in group C (r = 0.17).Conclusions. We conclude that lumen gain by balloon angioplasty is not related to the mode of atherosclerotic arterial remodeling. However, the mode of arterial remodeling affects the dilation mechanism.

A prescreening system for potential antiproliferative agents: implications for local treatment strategies of postangioplasty restenosis

Background. Recent advances in the understanding of the biology of restenosis indicate that it is predominantly caused by a multifactorial stimulation of smooth muscle cell proliferation. The aim of this study was to investigate the in vitro effect of five potential antiproliferative agents on smooth muscle cells from human atherosclerotic femoral arteries. Methods and results. Primary stenosing plaque material of 24 patients (aged 63 ± 14 years) and restenòsing plaque material of 7 patients (aged 65 ± 9 years) was selectively extracted from femoral arteries by the Simpson atherectomy device. Cells were isolated by enzymatic disaggregation and identified as smooth muscle cells by positive reaction with smooth muscle α-actin. Dalteparin sodium (0.001–100 anti-Xa units/ml), cyclosporine A (0.005–500 μg/ml), colchicine (0.00004–4 pg/ml), etoposide (0.002–200 μg/ml), and doxorubicin (0.0005–50 μg/ml) were added to the cultures. Six days after seeding, cells were trypsinized and cell number was measured by a cell counter. All five agents tested exhibited a significant inhibition of smooth muscle cell proliferation ( P < 0.001). After an incubation time of 48 h, the cytoskeletal components, α-actin, vimentin, and microtubules were investigated. At peak concentrations, all five tested agents except dalteparin sodium caused severe damage to the cytoskeleton. Conclusions. All five potential antiproliferative agents exhibited a significant inhibition of smooth muscle cell proliferation. The development of new intravascular delivery systems may open the way for local antiproliferative treatment strategies in interventional cardiology.

The dynamics of pulsatile flow in distensible model arteries1

Deposits and blockages are often found in the carotid, coronary, renal and femoral arteries. This paper deals with laser-Doppler velocity measurements in models of bifurcations of the human femoral arteries. Several models were prepared for the studies: a simplified 35 degrees glass model, two elastic-silicone-rubber models with a wall thickness of 1 mm and 2 mm, and true-to-scale rigid and elastic models. These measurements give a clearer picture of how hemodynamics influences the formation of atherosclerotic plaques where there is a hardening of the arterial walls and a loss of elasticity. In addition to the effects of elasticity, the influence of the flow's pulsatility were studied. The measurements were done in steady and pulsatile flow. From the velocity measurements the shear stresses were calculated.

Velocity profile distribution along an arterial vessel: way to improve detection of stenotic sites.

The influence of an arterial stenosis on the pattern of blood velocity spatial distribution is investigated. The blood velocity field in a human femoral artery in a stenotic state is computed by means of numerical simulation. Four distributions of velocity profiles along the vessel are shown, corresponding to four different instants of the cardiac cycle. The shape of the spatial pattern of the velocity profile is strongly perturbed by the stenosis: disturbances are so clear that an easy, precise localisation of the stenotic site is always possible, whatever instant of the cardiac cycle is considered. The reported results prove that a three-dimensional view of the velocity profile distribution along the vessel best emphasises the relevant haemodynamic information from a diagnostic point of view.

Paradoxical Arterial Wall Shrinkage May Contribute to Luminal Narrowing of Human Atherosclerotic Femoral Arteries

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. 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). 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.

Statin-fibrates combination therapy in hyperlipidemia

The role of mevalonate and its products (isoprenoids) in the control of cellular proliferation was examined by investigating the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (vastatins) on growth and on cholesterol biosynthesis of cultured arterial myocytes (SMC). Simvastatin (S) and fluvastatin (F), but not pravastatin (P), decreased the rate of growth of rat vascular SMC. The inhibition, evaluated as cell number, was dose-dependent with IC50 values of 2.8 and 2.2 μM for S and F, respectively; P (1–500 μM) was inactive. The inhibition of cell growth induced by 3.5 μM S (70% decrease) was prevented completely by the addition of 100 μM mevalonate, partially (70–85%) by the addition of 10 μM geraniol, 10 μM farnesol and 5 μM geranylgeraniol, but not by the addition of squalene, confirming the specific role of isoprenoid metabolites in regulating cell proliferation. All the tested vastatins inhibited the incorporation of [14C]acetate into cholesterol but P had 800 times lower potency than S and F. Similar results were obtained in SMC from human femoral artery. At least 80% inhibition of cholesterol synthesis was necessary to induce a decrease in SMC proliferation. To further investigate the relationship between cholesterol synthesis and cell growth, two enantiomers of F were investigated. The enantiomer more active on HMG-CoA reductase was 70- and 1.6-fold more potent on arterial myocyte proliferation than its antipode and the racemic mixture, respectively. A similar IC50 proliferation/cholesterol synthesis ratio for all the inhibitory vastatins (S, F and its enantiomers), regardless of their different potency, supports a causal relationship between the mevalonate synthetic pathway and cell proliferation.

Effects of cytokines on the expression of cell adhesion molecules by cultured human omental mesothelial cells.

Cultured mesothelial cells (HOMES) are very responsive to the proinflammatory cytokines, interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha). E-selectin, ICAM-1 and VCAM-1 are known to play an important role, because they are presented by diverse cell types, for example endothelial cells (ECs), and interact with co-responding ligands on white blood cell membranes. In this study, the expression of ICAM-1, VCAM-1, E-selectin as well as PECAM-1 on cultured HOMES was studied over 5, 24, 48 and 72 h exposure to IL-1 beta, interferon-gamma and TNF-alpha. In previous studies we have shown that IL-1 beta and TNF-alpha increase the expression of ICAM-1, E-selectin and VCAM-1 on the cytoplasmatic membranes of HUVECs, HSVECs and HAFECs (ECs from human umbilical vein, saphenous vein and femoral artery, respectively). Using a comparative quantitative cell enzyme immunoassay, we found that expression of the adhesion molecules ICAM-1 and VCAM-1 was significantly increased on HOMES in a dose- and time-dependent manner, compared to nonstimulated cells. Thus, ICAM-1 increased dramatically after 5 h incubation with TNF-alpha. Values of about 450% of the control level were measured. VCAM-1 was similarly stimulated after 24 h incubation with the same cytokine, although its level of expression was significantly lower than that of ICAM-1. In contrast to findings in the literature, VCAM-1 was not found to be expressed constitutively. E-selectin was neither constitutively expressed nor markedly inducible on HOMES. Only weak expression was found after 24 h incubation with high-dose IL-1 beta. PECAM-1 was expressed constitutively, as became evident in antibody dilution studies. These data indicate that HOMES respond to inflammatory stimuli, in some ways in a similar fashion to vascular endothelial cells, but also show a specific pattern of antigen presentation. The results are important for a better understanding of inflammatory processes in serous cavities. The data are also relevant for the improvement of antithrombogenous surfaces of the lumina of vascular prostheses by cell seeding.

Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination of cholesterol from human macrophages.

27-Hydroxycholesterol was found in surprisingly high amounts in atherosclerotic human femoral arteries. When human macrophages were cultured in a medium containing serum, there was a significant transfer of 27-hydroxy-cholesterol and 3 beta-hydroxy-5-cholestenoic acid from the cells into the medium. Sterol 27-hydroxylase (EC 1.14.13.15) is likely to be responsible for formation of the two products as shown by use of immunoblotting, a specific inhibitor, and the 18O-labeling technique. Sterol 27-hydroxylase has the unusual ability to hydroxylate the same methyl group three times to give a carboxylic acid; thus, 3 beta-hydroxy-5-cholestenoic acid is likely to be a direct product of the enzyme. The production of these steroids increased after addition of cholesterol to the culture medium. By using deuterium-labeled cholesterol, it was ascertained that most of the oxidized products were formed from exogenous cholesterol taken up by the cells. 27-Hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid are present in the circulation and are efficiently converted into bile acids in human liver. It is suggested that conversion of cholesterol into 27-hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid represents a general defence mechanism for macrophages and possibly also other peripheral cells exposed to cholesterol. Absence of this defence mechanism may contribute to the premature atherosclerosis known to occur in patients with sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis).

Intravascular Ultrasound: Value of Electronic and Mechanical Devices for Quantifying Mild to Moderate Atherosclerosis

To define the accuracy of electronic and mechanical ultrasound (US) devices for determining the thickness of intima and media, 32 fresh normal and atherosclerotic human femoral arteries were obtained at necropsy. The samples were imaged with a 64-element array and a mechanically rotating US transducer at 20 MHz. The mean thickness of the intimal and medial layer was measured with electronic calipers followed by histopathologic and micromorphometric analysis. Morphometric correlation for intima showed r = 0.64 for the electronic and r = 0.58 for the mechanical US device. The correlation between ultrasonic and histologic measurement of medial thickness in normal and diseased specimens was r = 0.79 for the multielement and r = 0.76 for the mechanical transducer. In conclusion, multielement array transducers are equivalent to mechanically driven probes in the quantitative assessment of peripheral arterial wall layers. Both systems lack sufficient accuracy in the determination of mild to moderate intimal thickening.

Arterial imaging with a new forward-viewing intravascular ultrasound catheter, II. Three-dimensional reconstruction and display of data.

Current intravascular ultrasound (IVUS) catheters provide transverse imaging at the level of the ultrasound transducer. This limits imaging to large-diameter segments without critical atherosclerotic narrowings. We have developed a prototype 20-MHz forward-viewing IVUS catheter that provides two-dimensional sector imaging distal to the catheter tip. A present limitation of this technique is that the catheter must be manually rotated to obtain multiple longitudinal views required to integrate the segment into a three-dimensional matrix. To overcome this, we have developed an algorithm that reconstructs these multiple two-dimensional forward-viewing IVUS images into a three-dimensional matrix for more complete depiction of the segment distal to the ultrasound catheter. This algorithm allows display and multidimensional slicing of the three-dimensional reconstruction. METHODS AND RESULTS. To test our algorithms, five arterial segments (three canine aortas, two human femoral arteries) were evaluated in vitro. In each segment, 36 forward-viewing longitudinal slices were collected, digitized, processed, and reoriented to produce a three-dimensional reconstruction (3DR) matrix. The matrix data were sliced into parallel transverse sections and compared with morphometric interpretation of histological sections (Histo). As a result, image data could be reconstructed for a distance of 2.0 cm ahead of the catheter. 3DR easily demonstrated wall and luminal morphology and provided transverse IVUS images comparable to the histological specimens. A good correlation was noted between Histo- and 3DR-determined luminal diameters (LD) and luminal areas: 3DR LD = 1.4 Histo LD-0.4, r = .86; 3DR LD = 0.7 +/- 0.20 cm (mean +/- SD); and Histo LD = 0.7 +/- 0.13 cm. These preliminary data demonstrate the feasibility of 3DR of forward-viewing IVUS data. This method allows rapid, detailed analysis of diseased arterial segments previously unavailable with standard IVUS and may permit better targeting of interventional techniques.

Arterial imaging with a new forward-viewing intravascular ultrasound catheter, I. Initial studies.

Intravascular ultrasound (IVUS) of arteries is limited by the inability of current instruments to visualize beyond the catheter tip. We have developed a prototype 4-mm-diameter forward-viewing IVUS catheter (Cardiovascular Imaging Systems, Sunnyvale, Calif) that has the ability to provide B-mode cross-sectional ultrasound data for a distance of up to 2 cm distal to the catheter tip. To study the utility of this device, a 20-MHz forward-viewing IVUS catheter was used to examine 13 arterial segments (5 human femoral arteries, 1 human carotid artery, 7 canine arteries) in vitro and 1 phantom. After imaging, all data were compared with histology (Histo). In all cases, the IVUS catheter provided forward-viewing images corresponding to the arterial geometry and demonstrated vascular landmarks and atherosclerotic lesions. There was a good correlation between Histo-determined luminal diameters (LD) and IVUS-determined diameters for a distance of 14 mm ahead of the catheter tip: IVUS LD = 1.0 Histo LD + 1.3 (r = .87). These preliminary data suggest that a forward-viewing IVUS catheter is feasible, accurate, and useful for evaluation of arterial geometry distal to the catheter tip.

Cytokeratins 8 and 18 in smooth muscle cells. Detection in human coronary artery, peripheral vascular, and vein graft disease and in transplantation-associated arteriosclerosis.

During development of atherosclerotic lesions, vascular smooth muscle cells (SMCs) undergo changes both phenotypically and in their cytoskeleton composition. An expression of cytokeratins 8 and 18 in SMCs in plaques of the human superficial femoral artery and of cytokeratin 8 in lesions of the aorta was recently described. Since cytokeratins are epithelial markers generally not found in normal adult vascular SMCs, we performed a detailed immunofluorescence microscopy study using a large panel of antibodies against the various cytokeratin polypeptides and other elements of the cytoskeleton. We included lesions of carotid, common and superficial femoral, iliac, and popliteal arteries; the abdominal aorta; and saphenous vein bypass grafts, as well as primary, restenotic, and transplantation-associated lesions of coronary arteries (n = 33). Cytokeratins 8 and 18 were present in myointimal cells of all pathological specimens. Colocalization with smooth muscle alpha-actin identified most cytokeratin-positive cells as SMCs. Only very few cells cosynthesized cytokeratin and desmin, whereas the majority of cytokeratin-positive cells were vimentin-positive. This pattern of cytoskeletal protein synthesis is similar to that found in some fetal and/or neonatal SMCs. These findings suggest that the synthesis of cytokeratins in a subset of SMCs of atherosclerotic lesions is a common phenomenon in coronary artery and peripheral vascular disease as well as graft disease and transplantation-associated arteriosclerosis and that the state of these SMCs is of a "dedifferentiated" fetal type.

Numerical studies of three-dimensional arterial flows in reverse curvature geometry: Part I--Peak flow.

A three-dimensional flow simulation at Repeak = 192 and 580 was made in a smooth reverse curvature model that conformed to the gentle "S" shape from a human left femoral artery angiogram. The objective of this numerical investigation was to find the changes in pressure, shear stress, velocity profile, and particle path occurring in the double-curved arterial vessel. Due to the impingement of blood at the outer wall in the first bend region, the wall shear stress approached 40 dyne/cm2--a value over twice as large as in the straight upstream segment. Conversely, at the inner wall in the first bend, a low shear stress region was found where the value of the shear stress was consistently smaller than that in the straight section. The initiation of centrifugal effects caused by the first bend could clearly be seen at Repeak = 580, but due to the close proximity of the reverse curvature segment, the momentum effect due to the second bend overshadowed the centrifugal effect. Hence, only near the end of the second bend did the centrifugal effect due to the second bend result in a double-spiral-secondary motion. In addition, the numerically calculated pressure drop data were in agreement with prior experimental values.

Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase

The role of mevalonate and its products (isoprenoids) in the control of cellular proliferation was examined by investigating the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (vastatins) on growth and on cholesterol biosynthesis of cultured arterial myocytes (SMC). Simvastatin (S) and fluvastatin (F), but not pravastatin (P), decreased the rate of growth of rat vascular SMC. The inhibition, evaluated as cell number, was dose-dependent with IC 50 values of 2.8 and 2.2 μM for S and F, respectively; P (1–500 μM) was inactive. The inhibition of cell growth induced by 3.5 μM S (70% decrease) was prevented completely by the addition of 100 μM mevalonate, partially (70–85%) by the addition of 10 μM geraniol, 10 μM farnesol and 5 μM geranylgeraniol, but not by the addition of squalene, confirming the specific role of isoprenoid metabolites in regulating cell proliferation. All the tested vastatins inhibited the incorporation of [ 14C]acetate into cholesterol but P had 800 times lower potency than S and F. Similar results were obtained in SMC from human femoral artery. At least 80% inhibition of cholesterol synthesis was necessary to induce a decrease in SMC proliferation. To further investigate the relationship between cholesterol synthesis and cell growth, two enantiomers of F were investigated. The enantiomer more active on HMG-CoA reductase was 70- and 1.6-fold more potent on arterial myocyte proliferation than its antipode and the racemic mixture, respectively. A similar IC 50 proliferation/cholesterol synthesis ratio for all the inhibitory vastatins (S, F and its enantiomers), regardless of their different potency, supports a causal relationship between the mevalonate synthetic pathway and cell proliferation.