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How to assess coronary artery remodeling by intravascular ultrasound
Editorial
How to assess coronary artery remodeling by intravascular ultrasound Michael Schartl, MD and Wolfgang Bocksch, MD Berlin, Germany
Coronary artery remodeling is a type of the large spectrum of vessel remodeling and has been defined as geometrical and structural changes of the vessel wall during the development of atherosclerosis.1 In the early course of atherosclerosis, a radial enlargement of the vessel wall can compensate for plaque growth, thus postponing the development of flow-limiting luminal obstruction in the presence of significant plaque burden.2 In more advanced lesions, some vessels may shrink at the plaque site, aggravating rather than compensating for lumen loss.3 Therefore, the direction (expansion or constriction) and extent (inadequate or adequate ) of vascular remodeling in response to plaque growth determine the magnitude of lumen loss in the course of coronary atherosclerosis. Intravascular ultrasound (IVUS) provides a tomographic image of an artery that permits estimation of the lumen area, plaque area, and vessel size, which is equivalent with the external elastic membrane (EEM) area. The American College of Cardiology/European Society of Cardiology expert consensus document has stated that remodeling can be quantified with IVUS by static or serial approach in vivo.4 The static approach defines the remodeling process at a single time point. For this, it is necessary to compare vessel size at the lesion to an adjacent reference site, assuming that the original vessel size was similar at the lesion and reference site. However, the presumption has several limitations. The reference site might already be altered by remodeling, Independent of (eg, hypertension) or dependent on early atherosclerosis. Moreover, the extent of vessel tapering between lesion and reference site is unknown. Definitions used to quantify the remodeling process vary distinctly because of varying reference sites and the manner of adjusting for vessel tapering. Therefore, the different definitions have a significant impact on the incidence and determinants of remodeling patterns.5
From the Department of Cardiology, University Hospital Charite, Campus Virchow. Submitted January 25, 2006; accepted February 11, 2006. Reprint requests: Michael Schartl, MD, Department of Cardiology, Universitaetsklinikum Charite, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany. Am Heart J 2006;152:414- 6. E-mail: [email protected] 0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.02.027
Using a serial approach, the change in the EEM area of a lesion is determined by 2 measurements obtained at different time points at the same lesion site. Consequently, the remodeling process is quantified directly in contrast to the static approach, which allows only an indirect quantification. The presence of multiple methods for defining and quantifying remodeling has created confusion in the field. In this issue of American Heart Journal, Sipahi et al6 provide fresh insight into the methodological limitations to assess arterial remodeling by IVUS. They report the result of a retrospective subanalysis of 210 focal coronary lesions using the IVUS database of the prospective REVERSAL trial to compare systematically the static and serial approach.7 The IVUS frame with the largest atheroma burden at baseline was used as the site for the assessment of remodeling. Follow-up measurements at 18 months were performed at the same site. To consider the time component for the static assessment, the remodeling index (RI = lesion EEM area/reference EEM area) was calculated at both baseline and follow-up. Using this approach, remodeling was categorized as expansive if RI was N1.05, as incomplete if RI was between 0.95 and 1.05, and as constrictive if RI was b0.95.4 For serial assessment, the ratio between EEM area at follow-up minus EEM area at baseline and atheroma area at follow-up minus atheroma area at baseline were calculated to analyze changes in lumen size. According to the American College of Cardiology/ European Society of Cardiology expert consensus document, a ratio of N1 was considered as expansive, 0 to 1.0 as incomplete, and b0 as constrictive.4 These definitions are applicable only for plaques that show progressing growth. Therefore, the authors have broadened the definitions in plaques with regression as constrictive if the ratio is N1, as incomplete if the ratio is 0 to 1, and as expansive for a ratio b0.6 Using the static approach, the remodeling index was significantly lower at follow-up (1.062 at baseline vs 1.027 at follow-up, P b .001), which could be interpreted as constrictive remodeling over time for all lesions. The serial approach showed that 51% of lesions had undergone expansive remodeling, 29% constrictive, and 20% incomplete remodeling. In summary, although most lesions had expansive remodeling on serial assessment, the remodeling index on static assessment decreased, suggesting constrictive remodeling.
American Heart Journal Volume 152, Number 3
The cross validation of the 2 methods is critical. Using the serial approach, the direction of remodeling for each individual lesion is estimated, whereas the static approach summarizes the remodeling process for the total group of lesions. In future studies, the comparability of the 2 methods may be improved by calculating the difference of the remodeling indices at baseline and at follow-up for each lesion individually. A positive difference would imply expansive and a negative difference restrictive remodeling. Sipahi et al6 found that the EEM area at the reference site increases to a greater extent than that at the lesion site within 18 months. This can partly explain the different results obtained by the 2 methods. But more importantly, this observation implies a further limitation for all static approaches because an unknown proportion of lesions classified as constrictive remodeling may, in fact, be lesions with expansively remodeled reference segments. Sipahi et al6 classified each lesion as constrictive, expansive, or incomplete remodeling using the static definition at follow-up and compared these results with the categorization using the serial definition. They found only a 39% concordance in the evaluation of the type of remodeling between the 2 methods. Accordingly, if one only had the follow-up IVUS and used the static approach, categorization using the remodeling index would be discordant with serial assessment in 61% of the cases. The poor concordance between the methods are related to 2 important differences used to characterize the remodeling process. First, the serial approach considers changes in plaque volume, whereas in the static approach, changes in plaque volume are neglected. As a result, considerable differences in the group of patients classified as incomplete remodeling exist between the 2 methods. The cutoff points of N1.05 and 0.95 in the static approach are related to a 95% CI to compensate for the assumption that the original vessel size was similar at lesion and reference site. Hence, the term incomplete remodeling should be replaced by no remodeling. The cutoff point in the serial approach is no change in EEM area. Therefore, the category bincomplete remodelingQ consists of a heterogenous group of patients having unfavorable outward expansion or favorable constriction in relation to changes in lumen size. Second, the serial approach describes the dynamic (extent and direction over time) process of remodeling, whereas the static approach describes only the extent of remodeling at a single time point. For instance, an outward remodeled lesion seen at a single time point may have undergone further enlargement or even shrinkage as a consequence of a drug effect. Remodeling is traditionally defined by using a single lesion frame. Therefore, 2-dimensional cross-sectional measurements were performed by Sipahi et al.6 However,
Schartl and Bocksch 415
the identification of the same site of a lesion by IVUS is difficult despite the usage of topographic landmarks and an automatic pullback system. The use of a volumetric approach can minimize errors for matching images at different time points, but a volumetric approach has to consider that remodeling is a 3-dimensional process and may vary over the length of a plaque with positive and negative remodeling appearing side by side.8 Sipahi et al6 found, at the lesion site, a significant correlation (r = 0.82, P b .001) between changes in atheroma area and in EEM area. The slope was 1.24, and the intercept with the EEM area axis, 0.45. The slope determines how much plaque area decreases the lumen and how much is accommodated by remodeling (compensatory size change). According to the definition in their serial approach, the authors concluded that a slope of 1.24 indicates that expansive (overcompensatory) remodeling was the prevailing remodeling pattern. However, this is only true for lesions having plaque progression. In patients having plaque regression, a slope of 1.24 indicates constrictive (unfavorable applied to the change in lumen size) remodeling. Therefore, looking at the total of all plaques in 1 analysis will lead inevitably to different results of drug-dependent remodeling processes, depending on plaque progression or regression. This disparate effect of the same drug is an unlikely scenario. This problem is resolved by calculating the regression line separately for plaque progression and regression in a lipid-lowering trial.9 In an interventional trial, changes in arterial size can occur dependent on or independent of changes in plaque size. A multiple regression model may differentiate the 2 eventualities.10 Theoretically, the slope of the regression line is the plaque-dependent term of remodeling, whereas the regression constant is the plaqueindependent term of remodeling.10 Consequently, the plaque-independent effect of an intervention can be categorized as constrictive (regression constant is negative) or expansive (regression constant is positive). Both the static and serial approach have been used to investigate the effect of cholesterol levels or lipidlowering therapy on coronary artery remodeling. As expected, the results are conflicting. Using a static approach, hypercholesterolemia was associated with expansive remodeling, but in a serial IVUS study, there was no difference in the annual changes of the EEM area between patients with high and low low-density lipoprotein cholesterol (LDL-C) levels.11,12 Hamasaki et al13 compared the results of 2 groups of patients treated with lipid-lowering therapy at a single time point and found that an adequate treatment of cholesterol was associated with outward remodeling. We investigated the effect of LDL-C levels in a longitudinal study using a multiple regression model and found that the outward remodeling process was diminished in patients with plaque progression and an LDL-C level b100 mg%9, which is in
American Heart Journal September 2006
416 Schartl and Bocksch
line with an observational study in which 1 year of treatment with simvastatin leads to a significant decrease in EEM area.14 Nicholls et al15 demonstrated that lipidlowering therapy is associated with expansive remodeling for lesions at coronary branch points but not at nonbranching sites, reflecting that the remodeling process varies at different regions. The variable results in patients with lipid-lowering therapy obtained with IVUS are related to differences in the study design and, especially, in the definition and quantification of the remodeling process. Therefore, it is time to reevaluate the standards of remodeling measurements in interventional trials. Ideally, such a study should be performed longitudinally and contain both a static and a serial analysis. The static analysis can inform us whether there is already arterial remodeling at baseline. The serial analysis should be performed by simultaneously measuring changes in vessel size in response to changes in plaque size at the same site of the lesion over time. This analysis will show us the extent and direction of remodeling and what happens to the lumen size for each lesion. Whether a multiple regression analysis allows to differentiate between plaquedependent and plaque-independent changes in the remodeling process has to be discussed.10
5.
6.
7.
8.
9.
10. 11.
12.
References 1. Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med 1994;330:1431 - 8. 2. Glagov S, Weisenberg E, Zaris CK, et al. Compensatory enlargement of human artherosclerotic coronary arteries. N Engl J Med 1987;316:13371 - 5. 3. Pasterkamp G, Wensing PJ, Post MJ, et al. Paradoxical arterial wall shrinkage may contribute to luminal narrowing of human atherosclerotic femoral arteries. Circulation 1995;91:1444 - 9. 4. Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology Clinical Expert Consensus Document on Standards for
13.
14. 15.
Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478 - 92. Hibi K, Ward MR, Honda Y, et al. Impact of different definitions on the interpretation of coronary remodeling determined by intravascular ultrasound. Catheter Cardiovasc Interv 2005;65:233 - 9. Sipahi I, Tuzcu EM, Schoenhagen P, et al. Static and serial assessments of coronary arterial remodeling are discordant: an intravascular ultrasound analysis from the REVERSAL trial. Am Heart J 2006;152:544 - 50. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid lowering therapy on progression of coronary atherosclerosis. JAMA 2004;291:1071 - 80. Schoenhagen P, Ziada KZ, Vince G, et al. Arterial remodeling and coronary artery disease: the concept of dilated versus obstructive coronary atherosclerosis. J Am Coll Cardiol 2001;38: 297 - 306. Schartl M, Bocksch W, Fateh-Moghadam S, on behalf of the GAIN Study Group. Effects of lipid lowering therapy on coronary artery remodeling. Coron Artery Dis 2004;15:45 - 51. Schwartz RS, Topol EJ, Serruys PW, et al. Artery size, neointima and remodeling. J Am Coll Cardiol 1998;32:2087 - 94. Tauth J, Pinnow E, Sullebarger JT, et al. Predictors of coronary arterial remodeling patterns in patients with myocardial ischemia. Am J Cardiol 1997;80:1352 - 5. Birgelen C, Hartmann M, Mintz GS, et al. Relation between progression and regression of atherosclerotic left main coronary artery disease and serum cholesterol levels as assessed with serial long-term follow-up intravascular ultrasound. Circulation 2003;108:2757 - 62. Hamasaki S, Higano ST, Suwaidi JA, et al. Cholesterol-lowering treatment is associated with improvement in coronary vascular remodeling and endothelial function in patients with normal or mildly diseased coronary arteries. Arterioscler Thromb Vasc Biol 2000;20:737 - 43. Jensen LO, Thayssen P, Pedersen KE, et al. Regression of coronary atherosclerosis by simvastatin. Circulation 2004;110:265 - 70. Nicholls S, Tuzcu EM, Schoenhagen P, et al. Effect of atorvastatin versus pravastatin on arterial remodeling at coronary brach points (from the REVERSAL Study). Am J Cardiol 2005;96:1636 - 9.
How to assess coronary artery remodeling by intravascular ultrasound Michael Schartl, MD and Wolfgang Bocksch, MD Berlin, Germany
Coronary artery remodeling is a type of the large spectrum of vessel remodeling and has been defined as geometrical and structural changes of the vessel wall during the development of atherosclerosis.1 In the early course of atherosclerosis, a radial enlargement of the vessel wall can compensate for plaque growth, thus postponing the development of flow-limiting luminal obstruction in the presence of significant plaque burden.2 In more advanced lesions, some vessels may shrink at the plaque site, aggravating rather than compensating for lumen loss.3 Therefore, the direction (expansion or constriction) and extent (inadequate or adequate ) of vascular remodeling in response to plaque growth determine the magnitude of lumen loss in the course of coronary atherosclerosis. Intravascular ultrasound (IVUS) provides a tomographic image of an artery that permits estimation of the lumen area, plaque area, and vessel size, which is equivalent with the external elastic membrane (EEM) area. The American College of Cardiology/European Society of Cardiology expert consensus document has stated that remodeling can be quantified with IVUS by static or serial approach in vivo.4 The static approach defines the remodeling process at a single time point. For this, it is necessary to compare vessel size at the lesion to an adjacent reference site, assuming that the original vessel size was similar at the lesion and reference site. However, the presumption has several limitations. The reference site might already be altered by remodeling, Independent of (eg, hypertension) or dependent on early atherosclerosis. Moreover, the extent of vessel tapering between lesion and reference site is unknown. Definitions used to quantify the remodeling process vary distinctly because of varying reference sites and the manner of adjusting for vessel tapering. Therefore, the different definitions have a significant impact on the incidence and determinants of remodeling patterns.5
From the Department of Cardiology, University Hospital Charite, Campus Virchow. Submitted January 25, 2006; accepted February 11, 2006. Reprint requests: Michael Schartl, MD, Department of Cardiology, Universitaetsklinikum Charite, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany. Am Heart J 2006;152:414- 6. E-mail: [email protected] 0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.02.027
Using a serial approach, the change in the EEM area of a lesion is determined by 2 measurements obtained at different time points at the same lesion site. Consequently, the remodeling process is quantified directly in contrast to the static approach, which allows only an indirect quantification. The presence of multiple methods for defining and quantifying remodeling has created confusion in the field. In this issue of American Heart Journal, Sipahi et al6 provide fresh insight into the methodological limitations to assess arterial remodeling by IVUS. They report the result of a retrospective subanalysis of 210 focal coronary lesions using the IVUS database of the prospective REVERSAL trial to compare systematically the static and serial approach.7 The IVUS frame with the largest atheroma burden at baseline was used as the site for the assessment of remodeling. Follow-up measurements at 18 months were performed at the same site. To consider the time component for the static assessment, the remodeling index (RI = lesion EEM area/reference EEM area) was calculated at both baseline and follow-up. Using this approach, remodeling was categorized as expansive if RI was N1.05, as incomplete if RI was between 0.95 and 1.05, and as constrictive if RI was b0.95.4 For serial assessment, the ratio between EEM area at follow-up minus EEM area at baseline and atheroma area at follow-up minus atheroma area at baseline were calculated to analyze changes in lumen size. According to the American College of Cardiology/ European Society of Cardiology expert consensus document, a ratio of N1 was considered as expansive, 0 to 1.0 as incomplete, and b0 as constrictive.4 These definitions are applicable only for plaques that show progressing growth. Therefore, the authors have broadened the definitions in plaques with regression as constrictive if the ratio is N1, as incomplete if the ratio is 0 to 1, and as expansive for a ratio b0.6 Using the static approach, the remodeling index was significantly lower at follow-up (1.062 at baseline vs 1.027 at follow-up, P b .001), which could be interpreted as constrictive remodeling over time for all lesions. The serial approach showed that 51% of lesions had undergone expansive remodeling, 29% constrictive, and 20% incomplete remodeling. In summary, although most lesions had expansive remodeling on serial assessment, the remodeling index on static assessment decreased, suggesting constrictive remodeling.
American Heart Journal Volume 152, Number 3
The cross validation of the 2 methods is critical. Using the serial approach, the direction of remodeling for each individual lesion is estimated, whereas the static approach summarizes the remodeling process for the total group of lesions. In future studies, the comparability of the 2 methods may be improved by calculating the difference of the remodeling indices at baseline and at follow-up for each lesion individually. A positive difference would imply expansive and a negative difference restrictive remodeling. Sipahi et al6 found that the EEM area at the reference site increases to a greater extent than that at the lesion site within 18 months. This can partly explain the different results obtained by the 2 methods. But more importantly, this observation implies a further limitation for all static approaches because an unknown proportion of lesions classified as constrictive remodeling may, in fact, be lesions with expansively remodeled reference segments. Sipahi et al6 classified each lesion as constrictive, expansive, or incomplete remodeling using the static definition at follow-up and compared these results with the categorization using the serial definition. They found only a 39% concordance in the evaluation of the type of remodeling between the 2 methods. Accordingly, if one only had the follow-up IVUS and used the static approach, categorization using the remodeling index would be discordant with serial assessment in 61% of the cases. The poor concordance between the methods are related to 2 important differences used to characterize the remodeling process. First, the serial approach considers changes in plaque volume, whereas in the static approach, changes in plaque volume are neglected. As a result, considerable differences in the group of patients classified as incomplete remodeling exist between the 2 methods. The cutoff points of N1.05 and 0.95 in the static approach are related to a 95% CI to compensate for the assumption that the original vessel size was similar at lesion and reference site. Hence, the term incomplete remodeling should be replaced by no remodeling. The cutoff point in the serial approach is no change in EEM area. Therefore, the category bincomplete remodelingQ consists of a heterogenous group of patients having unfavorable outward expansion or favorable constriction in relation to changes in lumen size. Second, the serial approach describes the dynamic (extent and direction over time) process of remodeling, whereas the static approach describes only the extent of remodeling at a single time point. For instance, an outward remodeled lesion seen at a single time point may have undergone further enlargement or even shrinkage as a consequence of a drug effect. Remodeling is traditionally defined by using a single lesion frame. Therefore, 2-dimensional cross-sectional measurements were performed by Sipahi et al.6 However,
Schartl and Bocksch 415
the identification of the same site of a lesion by IVUS is difficult despite the usage of topographic landmarks and an automatic pullback system. The use of a volumetric approach can minimize errors for matching images at different time points, but a volumetric approach has to consider that remodeling is a 3-dimensional process and may vary over the length of a plaque with positive and negative remodeling appearing side by side.8 Sipahi et al6 found, at the lesion site, a significant correlation (r = 0.82, P b .001) between changes in atheroma area and in EEM area. The slope was 1.24, and the intercept with the EEM area axis, 0.45. The slope determines how much plaque area decreases the lumen and how much is accommodated by remodeling (compensatory size change). According to the definition in their serial approach, the authors concluded that a slope of 1.24 indicates that expansive (overcompensatory) remodeling was the prevailing remodeling pattern. However, this is only true for lesions having plaque progression. In patients having plaque regression, a slope of 1.24 indicates constrictive (unfavorable applied to the change in lumen size) remodeling. Therefore, looking at the total of all plaques in 1 analysis will lead inevitably to different results of drug-dependent remodeling processes, depending on plaque progression or regression. This disparate effect of the same drug is an unlikely scenario. This problem is resolved by calculating the regression line separately for plaque progression and regression in a lipid-lowering trial.9 In an interventional trial, changes in arterial size can occur dependent on or independent of changes in plaque size. A multiple regression model may differentiate the 2 eventualities.10 Theoretically, the slope of the regression line is the plaque-dependent term of remodeling, whereas the regression constant is the plaqueindependent term of remodeling.10 Consequently, the plaque-independent effect of an intervention can be categorized as constrictive (regression constant is negative) or expansive (regression constant is positive). Both the static and serial approach have been used to investigate the effect of cholesterol levels or lipidlowering therapy on coronary artery remodeling. As expected, the results are conflicting. Using a static approach, hypercholesterolemia was associated with expansive remodeling, but in a serial IVUS study, there was no difference in the annual changes of the EEM area between patients with high and low low-density lipoprotein cholesterol (LDL-C) levels.11,12 Hamasaki et al13 compared the results of 2 groups of patients treated with lipid-lowering therapy at a single time point and found that an adequate treatment of cholesterol was associated with outward remodeling. We investigated the effect of LDL-C levels in a longitudinal study using a multiple regression model and found that the outward remodeling process was diminished in patients with plaque progression and an LDL-C level b100 mg%9, which is in
American Heart Journal September 2006
416 Schartl and Bocksch
line with an observational study in which 1 year of treatment with simvastatin leads to a significant decrease in EEM area.14 Nicholls et al15 demonstrated that lipidlowering therapy is associated with expansive remodeling for lesions at coronary branch points but not at nonbranching sites, reflecting that the remodeling process varies at different regions. The variable results in patients with lipid-lowering therapy obtained with IVUS are related to differences in the study design and, especially, in the definition and quantification of the remodeling process. Therefore, it is time to reevaluate the standards of remodeling measurements in interventional trials. Ideally, such a study should be performed longitudinally and contain both a static and a serial analysis. The static analysis can inform us whether there is already arterial remodeling at baseline. The serial analysis should be performed by simultaneously measuring changes in vessel size in response to changes in plaque size at the same site of the lesion over time. This analysis will show us the extent and direction of remodeling and what happens to the lumen size for each lesion. Whether a multiple regression analysis allows to differentiate between plaquedependent and plaque-independent changes in the remodeling process has to be discussed.10
5.
6.
7.
8.
9.
10. 11.
12.
References 1. Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med 1994;330:1431 - 8. 2. Glagov S, Weisenberg E, Zaris CK, et al. Compensatory enlargement of human artherosclerotic coronary arteries. N Engl J Med 1987;316:13371 - 5. 3. Pasterkamp G, Wensing PJ, Post MJ, et al. Paradoxical arterial wall shrinkage may contribute to luminal narrowing of human atherosclerotic femoral arteries. Circulation 1995;91:1444 - 9. 4. Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology Clinical Expert Consensus Document on Standards for
13.
14. 15.
Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478 - 92. Hibi K, Ward MR, Honda Y, et al. Impact of different definitions on the interpretation of coronary remodeling determined by intravascular ultrasound. Catheter Cardiovasc Interv 2005;65:233 - 9. Sipahi I, Tuzcu EM, Schoenhagen P, et al. Static and serial assessments of coronary arterial remodeling are discordant: an intravascular ultrasound analysis from the REVERSAL trial. Am Heart J 2006;152:544 - 50. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid lowering therapy on progression of coronary atherosclerosis. JAMA 2004;291:1071 - 80. Schoenhagen P, Ziada KZ, Vince G, et al. Arterial remodeling and coronary artery disease: the concept of dilated versus obstructive coronary atherosclerosis. J Am Coll Cardiol 2001;38: 297 - 306. Schartl M, Bocksch W, Fateh-Moghadam S, on behalf of the GAIN Study Group. Effects of lipid lowering therapy on coronary artery remodeling. Coron Artery Dis 2004;15:45 - 51. Schwartz RS, Topol EJ, Serruys PW, et al. Artery size, neointima and remodeling. J Am Coll Cardiol 1998;32:2087 - 94. Tauth J, Pinnow E, Sullebarger JT, et al. Predictors of coronary arterial remodeling patterns in patients with myocardial ischemia. Am J Cardiol 1997;80:1352 - 5. Birgelen C, Hartmann M, Mintz GS, et al. Relation between progression and regression of atherosclerotic left main coronary artery disease and serum cholesterol levels as assessed with serial long-term follow-up intravascular ultrasound. Circulation 2003;108:2757 - 62. Hamasaki S, Higano ST, Suwaidi JA, et al. Cholesterol-lowering treatment is associated with improvement in coronary vascular remodeling and endothelial function in patients with normal or mildly diseased coronary arteries. Arterioscler Thromb Vasc Biol 2000;20:737 - 43. Jensen LO, Thayssen P, Pedersen KE, et al. Regression of coronary atherosclerosis by simvastatin. Circulation 2004;110:265 - 70. Nicholls S, Tuzcu EM, Schoenhagen P, et al. Effect of atorvastatin versus pravastatin on arterial remodeling at coronary brach points (from the REVERSAL Study). Am J Cardiol 2005;96:1636 - 9.