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Published online before print August 31, 2004, 10.1148/radiol.2331030914
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(Radiology 2004;233:366-375.)
© RSNA, 2004

Ultrasonography

Vascular Remodeling in Atherosclerotic Femoral Arteries: Three-dimensional US Analysis1

Mariann Gyöngyösi, MD, PhD, Christoph Strehblow, MD, Markus Haumer, MD, Paul Wexberg, MD, BM, Wolfgang Sperker, MD, Stephan Lehr, BS, Dietmar Glogar, MD, FESC, Gerard Pasterkamp, MD, PhD and Erich Minar, MD

1 From the Divs of Cardiology (M.G., C.S., P.W., W.S., D.G.) and Angiology (M.H., E.M.), Depts of Internal Medicine II and Medical Computer Sciences, Section of Clinical Biometrics (S.L.), Univ of Vienna, Wahringer Gurtel 18–20, A-1090 Vienna, Austria; and Heart Lung Institute, Utrecht, the Netherlands (G.P.). Received Jun 10, 2003; revision requested Aug 26; revision received Dec 10; accepted Jan 13, 2004. Address correspondence to M.G. (e-mail: mariann.gyongyosi@univie.ac.at).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the various modes of vascular remodeling of atherosclerotic femoral arteries and determine the associations between type of arterial remodeling and clinical data (age, sex, and medical history) and inflammatory parameters.

MATERIALS AND METHODS: Intravascular ultrasonography (US) of the femoral arteries was performed in 50 patients with clinical symptoms of peripheral vascular disease. To determine the arterial remodeling mode (expansive remodeling [ER], involving compensatory enlargement of the artery, or constrictive remodeling [CR], involving vessel constriction during progression of atherosclerosis), the cross-sectional areas (CSAs) of the external elastic membrane (EEM), lumen, and plaque-plus-media were measured every 0.1 mm by using three-dimensional reconstruction. Clinical, laboratory, and intravascular US data were compared in the different remodeling groups (dominant ER, dominant CR, or mixed remodeling) by using analysis of variance supplemented by Tukey-Kramer tests. Multivariate analysis was performed to test independent variables predicting dominant ER.

RESULTS: Intravascular US revealed the parallel existence of ER and CR in all patients: Increases and decreases in EEM in response to plaque growth could be observed within the same artery. ER dominated in 13 (26%) patients, and CR dominated in 11 (22%) patients: At least 80% of EEM CSAs were higher or lower than the mean of the EEM CSAs of the segments proximal and distal to the lesion. Patients with dominant ER had higher levels of serum C-reactive protein (CRP) compared with levels in patients with dominant CR and patients with mixed remodeling (1.62 mg/dL ± 2.05 [standard deviation] vs 0.19 mg/dL ± 0.33 and 0.21 mg/dL ± 0.39, respectively, P < .005). Multivariate analysis revealed high CRP level to be a significant independent predictor for dominant ER (P < .01).

CONCLUSION: The parallel existence of ER and CR was found in all patients with peripheral atherosclerosis, with a dominance of vessel expansion in 26% of patients. Higher plasma CRP level was associated with dominant ER.

© RSNA, 2004

Index terms: Arteries, femoral, 922.12989 • Arteries, stenosis or obstruction, 922.721 • Arteries, US, 922.12989 • Arteriosclerosis, 922.721 • Ultrasound (US), intravascular, 922.12989


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Although noninvasive examinations of atherosclerotic arteries have increasingly replaced diagnostic conventional angiography and intravascular ultrasonography (US), intravascular US has the benefit of yielding tomographic images of the arteries that (a) allow determination of plaque shape and size, (b) enable precise measurements of lumen, vessel, and plaque sizes (1–4), and (c) reveal the different types of arterial remodeling.

The arterial remodeling mode is defined as expansive if the external elastic membrane (EEM) cross-sectional area (CSA) of the culprit lesion is larger than the EEM CSA of the proximal reference segment and constrictive if the EEM CSA of the lesion is smaller than the EEM CSA of the distal reference segment (Fig 1) (5–8). In the coronary arteries, the selection of the lesion is based on the area of greatest luminal narrowing and/or qualitative intravascular US parameters, such as spontaneous dissection or the presence of thrombus, that reveal the lesion with the greatest narrowing compared with the diameter of reference segments 1 cm proximal and distal to the lesion that contain no significant plaque mass.



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  		Figure 1. Schematic illustration of arterial remodeling types in coronary arteries in a single culprit lesion. Light-gray circles represent arterial lumen.

 
However, because compensatory enlargement of the artery in response to growing plaque begins in the very early phase of atherosclerosis, the reference segments with nonsignificant plaques might already have undergone a remodeling process, leading to bias in the selection of the reference segments. In diffusely diseased arteries such as those that are found in the setting of severe peripheral atherosclerosis, long arterial segments usually display significant luminal narrowing with undulating severity along the artery. In contrast to coronary arteries, in which arterial remodeling is classified into one of three remodeling types (expansive, constrictive, or neutral), peripheral arteries—according to results of histologic examination of arteries ex vivo and intravascular US of arteries in vivo—apparently can show both constrictive and expansive remodeling in the same segment (5).

To facilitate the study of segmental remodeling, three-dimensional (3D) intravascular US analysis, which avoids the bias involved in selecting the single culprit lesion and remodeled reference segments, can be used. Additionally, 3D analysis permits rapid automated evaluation of lumen and plaque volumes and dimensions on a large number of planar image sections (7); thus, it is ideally suited—and, to our knowledge, is currently the only method that can be used—for investigating the pattern of vessel remodeling throughout the entire length of an arterial segment in vivo.

In the coronary arteries, the direction of remodeling (positive or adaptive or expansive; negative or constrictive) is consistently associated with clinical presentation (6,7). Expansive remodeling has been correlated with plaque vulnerability and rupture leading to the acute coronary syndrome (6,7,9). Postmortem studies of coronary arteries have revealed complex remodeling patterns influenced by local factors, including inflammation and fibrosis (10).

Peripheral arterial disease is associated with low-grade inflammation, as determined by leukocyte activation; increased levels of fibrinogen, C-reactive protein (CRP), and interleukin-8; and endothelial dysfunction in the affected limb (11,12). Repeated episodes of ischemia, which occur each time the patient with claudication walks, may further enhance the inflammatory process in the blood vessels and hence may play a role in the progression of local vascular disease (13). It has been shown that intermittent claudication is associated with increased thrombin formation (13). Repeated episodes of acute exacerbation of chronically inflamed atherosclerotic tissue may be a trigger for endothelial erosion and destabilization of preexisting plaque that may evolve with superimposed thrombosis (14).

Therefore, the aims of the present study were to investigate the various modes of vascular remodeling of atherosclerotic femoral arteries and to determine associations between the type of arterial remodeling and clinical data (age, sex, and medical history) and inflammatory parameters.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patient Population
Between July 1999 and December 1999, patients with clinical symptoms of unilateral peripheral occlusive atherosclerotic disease in the femoral artery (below the groin and above the popliteal fossa) who underwent percutaneous femoral intervention at the Division of Angiology of the Department of Internal Medicine II of the University of Vienna were included in the study. The initial study population consisted of 65 consecutive patients. Exclusion criteria were severe calcified lesions preventing correct quantitative intravascular US analysis (10 patients) and the need for predilatation of the native lesion before intravascular US because of severe narrowing of the artery (five patients).

Thus, the present femoral intravascular US analysis involves data for 50 patients. Before femoral angiography, all patients underwent Doppler US imaging, and the Doppler index was calculated. At the time of the investigations, no patient was suspected of having bilateral occlusive peripheral artery disease. Intravascular US was performed primarily for clinical purposes to determine the severity of the atherosclerosis and the extent of the atherosclerotic plaque requiring invasive treatment. Diagnostic femoral angiography and intravascular US were performed by E.M., who had 20 and 6 years of experience in angiography and intravascular US, respectively. The intravascular US data were recorded by M.G., M.H., and C.S., who had 6, 6, and 3 years of experience in intravascular US, respectively. The clinical data were collected by M.G., M.H., and E.M. The study was approved by the institutional review committee, and all subjects gave their informed consent.

Risk factors for atherosclerosis (diabetes mellitus, hypertension, hypercholesterolemia, smoking, and a positive family history of coronary atherosclerosis), age, sex, indicators of chronic inflammation (serum levels of CRP, fibrinogen, and leukocytes), and atherosclerotic parameters (levels of total cholesterol, low-density lipoprotein, triglycerides, lipoprotein(a), and apolipoproteins A-I and B) were recorded for all (included and excluded) patients (M.G.). The ankle-brachial pressure index and the maximal walking distance of all patients were measured (M.H.) before femoral angiography and intravascular US.

Angiography and Intravascular US
All patients received 10 000 IU of heparin (Heparin Immuno; Baxter, Deerfield, Ill) intravenously before the procedures. Conventional femoral artery angiography was performed with an antegrade percutaneous approach by using a 7-F sheath (Medtronic, Minneapolis, Minn). Digital subtraction angiography with "road map" software (Phillips Medical Systems, Eindhoven, the Netherlands) was performed by injecting a nonionic contrast agent (iopamidol, Iopamiro; Gerot Pharmazeutika, Vienna, Austria) to locate the exact position of the most diseased segments.

After intraarterial administration of 100 µg of nitroglycerin (Perlinganit; Schwarz Pharma, Monheim, Germany), intravascular US was performed with mechanical 30-MHz imaging systems and 2.9-F catheters (Boston Scientific, Natick, Mass). The intravascular US catheter was advanced distally beyond the lesion over a guidewire with fluoroscopic control (Fig 2), an automatic motorized pull-back device (Boston Scientific) connected to the intravascular US catheter pulled the sonographic tip back within the catheter cover at a speed of 1 mm/sec, and images of the diseased segment were obtained during the automatic pull-back.



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  		Figure 2. Longitudinal view of position of sonographic tip, which continuously records the US signs of plaques, within intravascular US (IVUS) catheter.

 
The entire lesion (a substantial plaque mass could involve multiple lesions of similar severity) and the distal and proximal reference segments that contained less than 30% stenosis were analyzed. A 5.6-cm-long arterial segment with nonsignificant plaque mass and a relatively short focal lesion was also analyzed in one patient. All intravascular US images were recorded on videotape for subsequent off-line analysis.

Three-dimensional Intravascular US Analysis
Qualitative intravascular US analysis included characterizing the visual appearance of the femoral atherosclerotic lesion as that of a soft lesion, possible thrombus, calcification, spontaneous dissection, or eccentric plaque. Lesion characteristics were determined in accordance with the intravascular US guidelines of the American College of Cardiology (3).

All intravascular US data were analyzed quantitatively with a computer-based intravascular US analysis system (EchoPlaque 2; INDEC Systems, Mountain View, Calif) in off-line mode.

After the intravascular US recordings were digitized, the system automatically traced the continuous lumen and EEM borders (Fig 3). The CSAs of the lumen, EEM, and plaque-plus-media and the percentage area of stenosis (ie, plaque burden) were calculated in accordance with the intravascular US guidelines of the American College of Cardiology (3). When image quality was inadequate or when extensive acoustic shadow (>120° of the circumference) as a result of calcification was encountered, the EEM area was not assessed and these intravascular US cross sections were excluded from the analysis. CSAs for the lumen, plaque-plus-media, and EEM were automatically calculated by the EchoPlaque 2 software for each 0.1-mm interval by using 3D reconstruction.



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  		Figure 3. Three-dimensional intravascular US (IVUS) analysis: The lumen and EEM contours, measured in cross sections of 0.1 mm each (top [transverse view] and bottom left [longitudinal view]), are automatically delineated and displayed. Lumen and EEM CSAs in one segment are measured (top right [transverse view]). Plaque-plus-media CSA is calculated as difference between EEM CSA and lumen CSA. The plaque burden is then calculated (bottom right). Expansive remodeling in response to growing plaque can be observed in this segment (top right).

 
All qualitative intravascular US images were independently analyzed by two experienced observers (M.G. and C.S., who had 6 and 3 years of experience in qualitative intravascular US, respectively). Consensus was reached in the event of discrepancy after intraobserver and interobserver variabilities were determined. The quantitative 3D intravascular US analysis was performed by one observer (C.S., who had 3 years of experience in quantitative intravascular US).

Determination of Arterial Remodeling Type
The beginning and the end of each lesion were considered to be the locations where the plaque burden (ie, the ratio of plaque-plus-media CSA to EEM CSA, expressed as a percentage) exceeded 30%. Segments that were proximal and distal to but within 1 cm of the lesion and had a plaque burden of less than 30% were regarded as reference segments. The reference EEM CSAs were calculated as the mean values of the proximal and distal EEM CSAs (3).

The lumen, plaque-plus-media, and EEM were reconstructed graphically for each patient by using the automatically measured CSAs, including the CSAs for the lesion and the distal and proximal reference segments. So that we could determine the vascular remodeling mode, we calculated the proportions of the measured EEM CSAs of the entire artery that exceeded the reference EEM CSA.

Dominant expansive remodeling was diagnosed if at least 80% of the EEM CSAs of all the analyzed segments were greater than the reference EEM CSA.

Dominant constrictive remodeling was diagnosed if at least 80% of the EEM CSAs of all the analyzed segments were less than the reference EEM CSA.

The arbitrary level of 80% was chosen on the basis of the EEM CSA values in the reference segments and in the single 5.6-cm-long arterial segment with nonsignificant plaque (plaque burden <30%) that was analyzed in one patient because the minimum and maximum values of these EEM CSAs were within the mean ± 10% (Fig 2). Use of this 80% level was confirmed by our experience that it corrects the bias resulting from the measurement variations (6), normal biologic variations, and temporary changes (eg, vasospasm caused by intravascular US).

Laboratory Measurements
Before the angiographic procedure, 10-mL venous blood samples were obtained for analyses of leukocytes (with an automated blood count analyzer), CRP, total cholesterol, triglycerides, low-density lipoproteins, lipoprotein(a), apolipoproteins A-I and B, and fibrinogen. Serum CRP level was determined by using the N High Sensitivity CRP assay (Dade Behring, Marburg, Germany), which measures CRP concentrations within the overall range between 0.0175 and 110 mg/dL. Expected values for healthy individuals are 0.3 mg/dL or lower. Total cholesterol, triglycerides, and low-density lipoproteins were assayed with a Hitachi 911 analyzer (Roche Diagnostics, Indianapolis, Ind). Lipoprotein(a), apolipoproteins A-I and B, and fibrinogen were measured with a BN II analyzer (Dade Behring). As given by the manufacturers, the normal ranges are 150–200 mg/dL (3.88–5.17 mmol/L) for total cholesterol, less than 100 mg/dL (<2.59 mmol/L) for low-density lipoprotein, 50–172 mg/dL (0.56–1.94 mmol/L) for triglycerides, 0–30 mg/dL (0–0.3 g/L) for lipoprotein(a), 125–215 mg/dL (1.25–2.15 g/L) for apolipoprotein A-I, 55–125 mg/dL (0.55–1.25 g/L) for apolipoprotein B, and 180–390 mg/dL (5.29–11.47 µmol/L) for fibrinogen.

Statistical Analysis
Data are expressed as means ± standard deviations. The sample size was calculated at the {alpha} level of .05 and probability level of .9 and by using the mean and standard deviation of the EEM of the reference segments of all patients. The differences between the different remodeling groups in terms of the continuous parameters (ie, clinical and quantitative intravascular US data) were evaluated by using analysis of variance. The P values yielded by the global F test were corrected for multiplicity by using the method of Bonferroni-Holm. If an adjusted P value was smaller than .05, post-hoc tests were performed with the Tukey-Kramer method. This procedure controls the overall type I error at the level of 5%.

All continuous clinical and laboratory parameters were analyzed separately from each other because there were no associations between the parameters. Categorical data were expressed as percentages and analyzed by using the {chi}2 test. Differences between male and female patients and between older (>60 years) and younger (≤60 years) patients in terms of all clinical and laboratory data (for both included and excluded patients) and qualitative and quantitative intravascular US data (for only included patients) were tested with the unpaired t test.

Intra- and interobserver variabilities were determined by using repeated 3D intravascular US analysis and included random and systematic measurement variations. Both the intra- and interobserver variability measurements included the error involved in the repeated selection of diseased arterial segments and the error involved in the repeated measurements of the EEM CSAs (the largest parameter with the largest variation). So that we could evaluate intraobserver variability, one observer (M.G.) repeatedly analyzed 20 intravascular US images, and correlation between the repeatedly measured EEM CSAs was tested with linear regression analysis. The intercept and slope of the linear regression were calculated for each set of initial and repeat measurements. The distribution of these estimates serves as a measure of intraobserver variability (15).

So that we could evaluate interobserver variability, two observers (M.G., C.S.) analyzed 3D intravascular US measurements of 35 femoral lesions in separate sessions, and both observers categorized the involved segments into one of the three remodeling categories. Interobserver agreement was calculated with weighted {kappa} statistics (16).

Univariate and multivariate stepwise logistic regression analyses were performed to identify independent correlates for the presence of dominant expansive remodeling (the nominal dependent variable).

First, all potential risk factors (age, sex, and the atherosclerotic risk factors of altered levels of serum cholesterol, triglycerides, low-density lipoprotein, lipoprotein(a), and apolipoproteins A-I and B), inflammation parameters (fibrinogen, CRP, and leukocyte counts), and qualitative intravascular US data (the presence of soft plaque, spontaneous dissection, possible thrombus, calcification, and plaque eccentricity) were tested in univariate regression analyses. To avoid parameter selection bias, the confounding variables (ie, the quantitative intravascular US parameters) that had a direct association either with each other (eg, EEM volume, which depends on the lumen and the plaque-plus-media volumes, which in turn depend on the lesion length) or with the remodeling mode (eg, the EEM CSA that is included in the definition of dominant expansive remodeling) were excluded from the logistic regression analysis.

Second, multivariate stepwise logistic regression analysis was performed. Factors exhibiting a significant association (P < .05) in the multivariate analysis were regarded as significant predictors for dominant expansive remodeling.

A P value of less than .05 was considered to indicate a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Clinical Data
The mean age of the 50 patients was 71 years ± 10; 29 (58%) of the patients were men. The mean age of the 15 patients who were not examined with intravascular US before femoral intervention (ie, the patients who were excluded from the study) was 73 years ± 9; eight (53%) of these patients were men. No differences were found between the patients who underwent intravascular US and the patients who were excluded in terms of the clinical data: Diabetes mellitus was recorded in 21 (42%) of the 50 included patients (vs six [40%] of the excluded 15 patients), hypercholesterolemia was recorded in 39 (78%) of the included patients (vs 10 [67%] of the excluded patients), hypertension was recorded in 44 (88%) of the included patients (vs 11 [73%] of the excluded patients), a positive family history of coronary artery disease was recorded in 11 (22%) of the included patients (vs three [20%] of the excluded patients), smoking was recorded in 18 (36%) of the included patients (vs eight [53%] of the excluded patients), and angiographically proved coronary artery disease was recorded in 23 (46%) of the included patients (vs five [33%] of the excluded patients). The mean ankle-brachial index in the included patients was 0.57 ± 0.21 (vs 0.54 ± 0.21 in the excluded patients), and the maximal walking distance was 74 m ± 22 (vs 68 m ± 15 in the excluded patients).

No differences were found between the 50 patients who were examined with intravascular US and the 15 patients who were not in terms of the laboratory data (not included).

The mean angiographically determined lesion length was 58.1 mm ± 19.2 (range, 31–79 mm) in the patients who underwent intravascular US and 60.8 cm ± 22.3 (range, 35–80 mm) in the patients who did not undergo intravascular US before intervention (the excluded patients).

The mean ages of the 21 female and the 29 male patients who were included in the study were 73 years ± 9 and 70 years ± 10, respectively; this difference in mean age was not significant. No significant differences were found between the male and the female patients in terms of the clinical and laboratory data.

Assessment of Inter- and Intraobserver Variabilities of Intravascular US Measurements
For intraobserver variability, the mean, standard deviation, variance, and coefficient of variation, respectively, were 1.028, 0.104, 0.011, and 10.09% for the regression coefficients and 0.048, 0.005, 0.0003, and 10.10% for the intercept for the repeated measurements. The upper and lower levels of the 95% confidence intervals were 1.08 and 0.98 for the regression coefficients and 0.05 and 0.04 for the intercepts.

For interobserver variability, the weighted {kappa} was 0.81, with upper and lower 95% confidence interval levels of 0.99 and 0.62.

For the proximal and distal reference arterial segments, the mean ± standard deviation and variance of the EEM CSA values with the minimum and maximum EEM CSA values of all patients were 24.48 mm2± 1.93 and 3.24 with 22.1 and 25.5 mm2, respectively. Results of power calculation indicated that a sample size of 11 was necessary in each group to enable detection of a mean difference of 1.5 standard deviations by using a two-group t test with a 5% two-sided significance level between two remodeling groups. Similarly, the mean ± standard deviation and the variance with the minimum and maximum EEM CSA values of a 5.6-cm-long arterial segment in one patient with nonsignificant plaque were 24.94 mm2± 0.91 and 0.83 with 23.17 and 26.75 mm2, respectively.

Remodeling of Femoral Arteries
Graphic reconstruction of the vessels revealed the parallel existence of expansive remodeling and constrictive remodeling in the same artery in all patients (Figs 4–7): Different extents of increase and decrease in the EEM could be observed within the same artery. Vessel expansion dominated the arterial remodeling process in 13 patients (26%), while dominant vessel constriction was observed in 11 patients (22%) and mixed remodeling was observed in 26 patients (52%). Figures 4–7 show three regression curves in dominantly expansive remodeling, constrictive remodeling, and mixed remodeling, and the corresponding reconstructed lumen, plaque-plus-media, and EEM CSAs. Analysis of the individual association between plaque-plus-media CSA and EEM CSA revealed large variations in the correlation coefficients (range, 0.006–0.940) and regression coefficients (the slopes ranged between –0.08 and 1.36). Additionally, the same plaque-plus-media CSA was paralleled by different sizes of the EEM CSAs in the same patient, indicating that the type of remodeling is at least partially independent of plaque size (Figs 4–7).



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  		Figure 4. Graphic reconstructions of lumen ({bullet}), plaque-plus-media ({blacktriangleup}), and EEM ({blacksquare}) contours in five randomly selected patients and in 5.6-cm-long artery in one patient with nonsignificant plaque (bottom right graph) show different responses of the EEM to plaque growth. Dashed line represents reference EEM area. dist. = distal, prox. = proximal, ref. = reference segment.

 


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  		Figure 5. Left: Scatterplot with regression line depicts dominant expansive remodeling with high correlation (r = 0.788, P < .001, y = 8.17 + 0.93x) between plaque-plus-media CSA and EEM CSA in 76-year-old man. Right: Corresponding computer-assisted graphic reconstruction of the vessel (only the segment containing the lesion, not the reference segments) shows that at least 80% of the EEM CSAs are above the individual reference value (the mean EEM CSA, calculated as the mean value of the EEM CSAs in the proximal and distal reference segments).

 


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  		Figure 6. Left: Scatterplot depicts dominant constrictive remodeling of femoral artery with no significant correlation (r = 0.056, P > .5) between plaque-plus-media CSA and EEM CSA in 73-year-old woman. Right: Corresponding computer-assisted graphic reconstruction of the vessel (only the segment containing the lesion, not the reference segments) shows that at least 80% of the EEM CSAs are below the individual reference value.

 


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  		Figure 7. Left: Scatterplot with regression line depicts mixed remodeling with moderate correlation (r = 0.121, P < .05, y = 17.1 + 0.13x) between plaque-plus-media CSA and EEM CSA in 66-year-old man. Right: Corresponding computer-assisted graphic reconstruction of the vessel (only the segment containing the lesion, not the reference segments) shows EEM values both above and below the individual reference value.

 
Clinical Data and Arterial Remodeling
Tables 1 and 2 list the mean values for the three remodeling groups in terms of the clinical and laboratory results. The clinical data did not differ significantly among the three groups (Table 1). However, the plasma level of CRP was significantly higher in the patients with dominant expansive remodeling than in the patients with dominant constrictive remodeling or mixed remodeling (Table 2). No differences were found between male and female patients or between older and younger patients in terms of the type of remodeling or other qualitative and quantitative intravascular US data.


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  		TABLE 1. Clinical Characteristics of Patients with Different Arterial Remodeling Modes

 

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  		TABLE 2. Laboratory Data for Patients with Different Arterial Remodeling Modes

 
Qualitative and Quantitative Intravascular US Results in Different Types of Remodeling
Tables 3 and 4 list the qualitative and quantitative intravascular US data in patients with different dominant remodeling types. No differences were observed in terms of the qualitative intravascular US data (Table 3). However, significantly larger plaque-plus-media and EEM volumes were recorded for lesions exhibiting dominant expansive remodeling (Table 4).


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  		TABLE 3. Qualitative Intravascular US Parameters of Different Arterial Remodeling Modes of Peripheral Occlusive Arterial Disease

 

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  		TABLE 4. Quantitative Intravascular US Data for Patients with Different Arterial Remodeling Modes of Peripheral Occlusive Arterial Disease

 
The mean CSAs of the lumen, plaque-plus-media, and EEM in the proximal and distal reference segments were similar in all three groups, with an obvious trend toward significantly higher plaque-plus-media CSAs and plaque burden in either the proximal or the distal reference segments in the case of dominant expansive remodeling. In the cases of dominant expansive remodeling, dominant constrictive remodeling, and mixed remodeling, respectively, the mean EEM CSAs in the distal reference segment were 11.6 mm2± 3.5, 7.4 mm2± 2.5, and 10.6 mm2± 2.9 (P < .1); the mean EEM CSAs in the proximal reference segment were 10.3 mm2± 2.7, 8.4 mm2± 2.3, and 9.2 mm2± 2.2 (P < .1); the mean plaque burdens in the distal reference segment were 29.0% ± 9.2, 28.5% ± 11.9, and 25.2% ± 10.6 (P < .1); and the mean plaque burdens in the proximal reference segment were 29.0% ± 8.1, 24.7% ± 10.8, and 22.5% ± 9.3 (P < .1).

Correlations between Dominant Expansive Remodeling and Intravascular US, Laboratory, and Clinical Data
Univariate analysis revealed an association between the presence of dominant expansive remodeling and serum CRP level (P < .01), fibrinogen level (P < .1), and leukocyte count (P < .1). In the multivariate analysis, CRP level proved to be the only significant predictor (P < .01) for dominant expansive remodeling.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
We observed the parallel existence of sequential expansive remodeling and constrictive remodeling in all patients with peripheral occlusive arterial disease, with dominance of the expansive remodeling or constrictive remodeling pattern in 48% of patients, and found that a high level of CRP is a significant predictor for the presence of dominant expansive remodeling.

Compensatory enlargement of the arteries in response to growing plaque has been observed in postmortem studies by Glagov et al (17). Furthermore, Pasterkamp et al (18) observed paradoxic arterial wall shrinkage contributing to luminal narrowing in the femoral arteries at ex vivo and in vivo examinations; these findings were also confirmed by Vink et al (19). As pointed out in a previous report (5), pooling all the data on plaque-plus-media and EEM size from all subjects may mask individual variations in the susceptibility of the artery to undergo compensatory enlargement and any relationship between arterial size and minimum plaque load; thus, without pooling the data, we calculated individual regression plots for all 50 patients. In accordance with the results of Pasterkamp et al (18), we found large variations in the correlation coefficients, regression coefficients (slopes), and levels of significance between plaque-plus-media size and EEM size.

Interestingly, all of our patients with femoral atherosclerotic disease exhibited both expansive remodeling and constrictive remodeling patterns to various extents; we did not observe pure expansive or pure constrictive remodeling in any patient. The individual regression plots revealed that the same plaque-plus-media size was associated with different EEM sizes, indicating that EEM size is at least partially independent of plaque size. It seems that arterial remodeling varies from site to site along the vessel, suggesting a rather local influence of various vasodilatative or vasoconstrictive factors. It may be assumed that focal differences in blood flow velocity and shear stress induce different degrees of vasodilatation (20–22).

In contrast with the remodeling modes of the coronary arteries, the parallel existence of expansive remodeling and constrictive remodeling of the peripheral arteries seems to be a common phenomenon; altered hemodynamic and vessel characteristics and differences in ability to achieve collateralization that overbridges severe stenoses might possibly explain the discrepancies. By using intravascular elastography, de Korte et al (23) observed significantly (P = .019) different local strain values between the femoral and the coronary arteries. van Lankeren et al (20) found that the contribution of the vessel area decrease to the lumen area reduction seen at the most stenotic site was lower in peripheral femoral arteries (52%) than in coronary arteries (67%–88%). These facts might contribute to the partially different reactions of coronary and femoral arteries to atherosclerosis and inflammation.

Expansive remodeling is connected with plaque vulnerability in the coronary vessels. In the femoral arteries, we found no signs of high-risk plaque in association with expansive remodeling. However, on the basis of the above-mentioned pathophysiologic differences between the coronary and the femoral arteries and the fact that femoral arteries exhibit all types of vessel remodeling, similar signs of unstable plaque that would result in acute femoral ischemia followed by tissue necrosis (similar to the acute coronary syndrome) cannot be expected.

One of the most important findings in our study is that an elevated plasma CRP level predicted the dominance of expansive remodeling. In patients with peripheral atherosclerotic disease, the presence of a low-grade inflammatory status is evidenced by the finding of elevated levels of fibrinogen, CRP, and interleukin-8 (8,24). Silvestro et al (25) reported a negative relationship between plasma levels of high-sensitivity CRP and endothelium-dependent flow-mediated vasodilatation in the brachial artery; this suggests that in patients with peripheral atherosclerosis, the higher the inflammatory status, the greater the endothelial dysfunction. Ridker et al (26) concluded that CRP levels provided additional prognostic information in comparison with standard lipid measurements in the setting of developing peripheral arterial disease.

Additionally, a high level of CRP has been found to be an independent risk factor for restenosis of femoropopliteal arteries (27) and for thrombotic complications in acute coronary syndromes (28–32). Interestingly, the level of CRP (although it is relatively low, representing chronic rather than acute inflamma-tion) in patients with peripheral vascular disease does not differ from that observed in patients with unstable angina (14,26).

Complex plaque anatomy, plaque rupture, and a high macrophage count have been demonstrated to be more frequent in the presence of marked outward remodeling (9,10,33). Thus, it might be assumed that an elevated CRP level reflects inflammation along the arterial system that leads to expansive remodeling of the arteries.

We used 3D intravascular US measurements to depict the sequential remodeling processes along the femoral artery. The EchoPlaque 2 program used in this study enables very fine segmentation; the program permitted cross-sectional measurements every 0.1 mm. This might have resulted in a more sensitive analysis of the changes in vessel and lumen areas than that achieved in previous studies involving the use of 200 segments per patient (34) or the selection of cross sections at 0.2-mm (35), 0.5-cm (18), or 1–2-cm (20) intervals.

The selection of the reference site is of crucial importance in terms of the interpretation of the results. Because peripheral atherosclerosis is very diffuse, it is difficult to find a reference segment with no significant lesion. For this reason, we selected the reference sites proximal and distal to the lesion in accordance with the intravascular US guidelines of the American College of Cardiology (3) as the cross sections that contained the least nonsignificant amount of plaque (plaque burden, <30%), assuming that at these sites the degree of wall remodeling is lowest and the lumen best approximates the original lumen (18).

There were limitations to this study. Because the acoustic shadowing involved a relatively small arc (<90°), planimetry of the cross sections was performed by extrapolating from the closest identifiable EEM borders, although this reduced the accuracy and reproducibility of the measurements. To define dominant remodeling, we used the EEM CSAs in the proximal and distal reference sites, although these sites included some nonsignificant plaque and might also have undergone remodeling. The superficial femoral artery tapers at the adductor canal, resulting in a smaller vessel diameter at the distal part of the artery and influencing the classification of the arterial remodeling mode. However, substantial tapering in the measured 8–10-cm femoral arterial segment may be discounted.

The dominance of remodeling was determined when at least 80% of all EEM CSAs were larger (dominant expansive remodeling) or smaller (dominant constrictive remodeling) than the mean value of the EEM CSAs in the proximal and distal reference segments. The arbitrary choice of a level of 80% might lead to bias, but with the use of other cutoff points between 70% and 90%, no reclassification of patients as having other remodeling dominance types was necessary. Moreover, this value was established on the basis of the minimum (–10%) and maximum (+10%) deviations of the mean EEM CSAs of the segments with a plaque burden of less than 30%. The compensatory phase of arterial remodeling starts in the early phase of atherosclerosis, but lumen narrowing of less than 30% still does not result in a substantial change in vessel size (18).

Because (to our knowledge) there has been no targeted investigation into the possible modes of vascular remodeling of normal, nondiseased femoral arteries, one might suspect that the changes in EEM documented in this study are merely a manifestation of normal variability in vascular caliber along the artery. However, nondiseased vascular segments did not display any focal constriction or expansion resulting in an undulation of the vessel size. Similarly, it might be assumed that the remodeling represents a virtual change in lumen shape if the intravascular US catheter tip is not perpendicular to the vessel wall. But because the intravascular US tip is placed and pulled back within the intravascular US catheter cover, which lies parallel to the artery, the intravascular US catheter tip is always perpendicular to the arterial wall (Fig 2).

The introduction of the intravascular catheter might cause a temporary vessel spasm, which influences the measured vessel dimensions. However, only a low incidence (1.1%–8.3%) of vessel spasm, which could always be resolved by administration of nitroglycerin, has been reported (36,37). All of our intravascular US measurements were performed after nitroglycerin administration, and a temporary spasm was observed in two patients. The intravascular US data were analyzed after resolution of the vasospasm in these patients.

Remodeling is a time- and plaque-dependent process, and an intravascular US examination performed at one time point might not fully reveal the complex processes involved. However, investigating the time course of remodeling by performing repeated angiographic and intravascular US procedures in patients with occlusive peripheral atherosclerosis does not appear acceptable from an ethical point of view.


   FOOTNOTES
 
Abbreviations: CRP = C-reactive protein, CSA = cross-sectional area, EEM = external elastic membrane, 3D = three-dimensional

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, M.G.; study concepts, D.G., C.S., W.S., M.G.; study design, M.H., E.M., M.G., P.W.; literature research, C.S., W.S.; clinical studies, M.H., E.M., M.G., P.W.; data acquisition, M.H., C.S.; data analysis/interpretation, C.S., W.S., S.L.; statistical analysis, M.G., S.L.; manuscript preparation, M.G.; manuscript definition of intellectual content, M.H., D.G., G.P., E.M., P.W.; manuscript editing, C.S., W.S., G.P.; manuscript revision/review, M.H., C.S., W.S., S.L.; manuscript final version approval, M.G., E.M., G.P., D.G., S.L.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
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