(Stroke. 2001;32:1539.)
© 2001 American Heart Association, Inc.
Original Contributions |
Angiotensin-Converting Enzyme Inhibition With Enalapril Slows Progressive Intima-Media Thickening of the Common Carotid Artery in Patients With Non–Insulin-Dependent Diabetes Mellitus
From the Second Department of Internal Medicine, Kagawa Medical University School of Medicine, Kagawa, Japan (N.H., K.M., H.O., T.T., H.M., M.K.); Department of Internal Medicine, Takamatsu National Hospital, Kagawa, Japan (N.H., M.K., Y.H.); and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, Calif (N.H., J.A.K.).
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Abstract |
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Background and Purpose—Whether angiotensin-converting enzyme (ACE) inhibitors have any clinically significant antiatherogenic effects in humans remains unproven. We undertook a prospective randomized clinical trial of 98 patients with non–insulin-dependent diabetes mellitus (NIDDM) to examine the efficacy of ACE inhibition with enalapril for preventing intima-media (IM) thickening of the carotid wall as measured ultrasonographically.
Methods—Ninety-eight NIDDM patients were randomly assigned either to enalapril at 10 mg/d (n=48) or to a control group (n=50); the planned duration of the trial was 2 years. All patients were seen at baseline (study entry) and 2 subsequent formal annual evaluations, in addition to standard clinical management for NIDDM. IM thickening and vascular lumen diameters were determined for all patients on the basis of baseline and 2 subsequent annual evaluations with carotid ultrasonography. We performed an intent-to-treat analysis to assess changes in IM thickening over the course of the study.
Results—Annual IM thickening measurements of the right and left common carotid arteries were 0.01±0.02 and 0.01±0.02 mm/y in the enalapril-treated group and 0.02±0.03 and 0.02±0.02 mm/y in the control group, respectively (P<0.05). From regression analysis, annual IM thickening was found to be predicted by enalapril use, sex, and insulin use (F3,94=3.86, P=0.012). When we controlled for these other variables, enalapril use reduced annual IM thickening of right and left common carotid arteries by 0.01±0.004 mm/y relative to the control group over the course of this study.
Conclusions—Long-term treatment with an ACE inhibitor (enalapril) slows progressive IM thickening of the common carotid artery in NIDDM patients.
Key Words: angiotensin converting enzyme inhibitors • atherosclerosis • carotid artery • diabetes • ultrasonography
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Diabetes mellitus (DM) is an important risk factor for coronary artery disease, arteriosclerosis obliterans, and stroke.1 An increase in intima-media thickness (IMT) has been demonstrated in DM patients.2 3 DM and mean fasting glucose level have been found to be positively associated with increased IMT of the common carotid artery but not IMT of the internal carotid artery, and hypercholesterolemia has been found to be related to plaque in the internal carotid artery.4 5
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor antagonists have been used to prevent vascular smooth muscle cell (SMC) migration and growth, neointima formation, and accumulation of cholesterol in the aorta in experimental models.6 7 8 Bonithon-Kopp et al9 showed that long-term exposure to high levels of plasma ACE resulted in structural alterations in the arterial wall.
It is well known that ACE inhibitor has a therapeutic effect on DM nephropathy. However, Hosoi et al10 have reported that ACE may be a risk factor for the development of wall thickening of the carotid artery in patients with non–insulin-dependent diabetes mellitus (NIDDM), although the mechanism of increasing arterial wall thickness in DM has not been elucidated. Moreover, ACE inhibitor therapy has not been shown to reduce restenosis after balloon catheter–induced arterial injury in the clinical setting.11 Previous studies12 13 have investigated ACE inhibitor efficacy relative to the common carotid artery IMT, but with equivocal results. More recently, the Heart Outcomes Prevention Evaluation (HOPE) Study14 showed that treatment with ramipril, an ACE inhibitor, reduced the rates of death, myocardial infarction, stroke, coronary revascularization, cardiac arrest, and heart failure as well as the risk of complications related to diabetes and of diabetes itself. Whether ACE inhibition has any clinically significant antiatherogenic effect in humans remains unproven.
We undertook a prospective randomized longitudinal study of 98 NIDDM patients, the purpose of which was to examine the efficacy of ACE inhibition with enalapril for preventing intima-media (IM) thickening of the carotid wall as measured ultrasonographically.
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Subjects and Methods |
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Subjects and Study Protocol
At the outset of the study, 170 NIDDM patients, as established by World Health Organization criteria, were being seen at Kagawa Medical University and Takamatsu National Hospital (K.M., M.K., Y.H., H.M.). It was our intention to offer study entry to all of these patients. Exclusion criteria constituted prior or concurrent history of ACE inhibitor (n=14), prior or concurrent antiplatelet therapy (n=17), prior or concurrent anticoagulant therapy (n=11) (with n=7 patients reporting both antiplatelet and anticoagulant therapy), other history of ischemic events (n=16), or refusal to grant informed consent (n=21). The 98 remaining patients were randomly assigned either to the enalapril treatment group (n=48), with treatment consisting of enalapril at 10 mg/d, or the control group (n=50), who did not receive enalapril. Patients were classified as hypertensive if they had systolic blood pressure >160 mm Hg, diastolic blood pressure >95 mm Hg, and/or were taking antihypertensive medication. Patients were classified as hyperlipidemic if they had total cholesterol >220 mg/dL, LDL cholesterol >140 mg/dL, triglyceride >150 mg/dL, and/or were taking antihyperlipidemic medication. We used a simple randomization scheme with treatment assignment initially determined by computerized random number generation in a sequential manner and then provided to the clinical investigators in sealed envelopes. Demographic and clinical data were available on all patients. In this regard, patients were categorized as either nonsmokers (never smoked or quit >10 years previously) or smokers (current and recent past smokers) at baseline. All patients had been receiving
1 of the following:
sulfonylurea and/or acarbose for NIDDM, a
Ca2+ channel blocker and/or 
-blocker for
hypertension, and a 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA)
reductase inhibitor and/or clofibrate derivative for
hyperlipidemia. Baseline measurements were taken at
time of study entry; formal follow-up measurements were scheduled at 1
year and a minimum of 2 years after study entry. Protocol compliance
was assessed for each patient, both at the planned annual evaluation
periods and at each routine outpatient visit. Enalapril-treated
patients who stopped taking enalapril because of coughing side effects
or other reasons, control patients who started taking an ACE
inhibitor during the duration of the trial, or any patients
who had an ischemic event or started taking an antiplatelet
or anticoagulant drug during the duration of the trial were considered
protocol violators. Numbers of protocol violators were small: n=4
(8.3%) in the treatment group and n=3 (6%) in the control group. A
trial profile is given in the
Figure
.15
The trial protocol followed the principles outlined in the Declaration
of Helsinki.
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Carotid Ultrasonography Measurements
At baseline and at the 2 subsequent annual
evaluations, carotid 2-dimensional echo imaging was performed in all
patients with a 7.5-MHz transducer with an axial resolution of
<0.20 mm (SSD-650, Aloka [at Kagawa Medical University] or
SSH-160A, Toshiba [at Takamatsu National Hospital]). All
recordings were performed by a trained sonographer (N.H.) who
was blinded to the patient profiles and treatment assignment. With the
patient seated, 2-dimensional longitudinal images of the bilateral
extracranial carotid arteries were photographed (resolution=0.093
mm) at end-diastole, defined as the top of the R wave on a
simultaneous ECG. All measurements were done in the
morning.
Each photograph was loaded into a computer system (Macintosh Quadra 650) with a graphic scanner at 1200 pixels per inch. The National Institutes of Health Image program was used to analyze the morphology of right and left common carotid arteries. We selected a morphological landmark on the baseline image, and the follow-up images (at 12 months and at a minimum of 24 months from the study entry) were made at the same site. Measurements consisted of IMT, defined as the distance between the intimal and adventitial leading edges, and vascular lumen diameter, defined as the distance between the lumen-intimal edges of the near and far walls.16 Measurements were performed within the area from 20 to 30 mm proximal to the tip of the flow divider of the carotid bifurcation. For IMT we measured at 6 sites, including 3 on both the near and far walls, and for vascular lumen diameter we measured at those same sites in each artery. The respective average values were used for analysis. Atherosclerotic lesions of >1.0 mm in IMT were defined as plaques17 and were excluded from measurement. We calculated annual IM thickening (mm/y) of common carotid arteries as (End Point IMT-Baseline IMT)/Observation Interval, and we calculated annual change in vascular lumen diameter (mm/y) of common carotid arteries as (End Point Vascular Lumen Diameter-Baseline Vascular Diameter)/Observation Interval. Relative changes were calculated by normalizing by baseline values.
All readings of the images were performed by 1 physician (H.O.) who was blinded to patient treatment assignment, as well as the time sequence of images within each patient (baseline, year 1, or end point).
To estimate the reproducibility of IMT and vascular lumen diameter recordings (all by N.H.), carotid artery images were recorded 10 times within 1 day in a healthy volunteer. Intraday reproducibility was estimated from the coefficients of variation of the evaluations. Similarly, carotid artery images were also recorded once a day for 10 days in another healthy volunteer; interday reproducibility was then estimated from the coefficients of variation of these evaluations.
Blood Pressure Measurements
Blood pressure was measured at baseline and the 2
subsequent annual examinations with a mercury sphygmomanometer in a
standardized fashion, after 10 minutes of rest with the subject in the
supine position. Systolic and diastolic blood
pressures (mm Hg) were defined according to Korotkoff sounds I and V.
All blood pressure measurements were done just before carotid
ultrasound measurements and were performed by a physician who was
blinded as to the patients’ profiles and treatment
assignments.
Serum Glucose, Plasma Lipoprotein, and Glycosylated
Hemoglobin
Serum glucose (mg/dL), total
cholesterol (mg/dL), triglyceride (mg/dL), HDL
cholesterol (mg/dL), and glycosylated hemoglobin
(HbA1c) (%) were measured at baseline and the
subsequent annual follow-up clinical examinations. LDL
cholesterol (mg/dL) was calculated as Total
Cholesterol-(HDL
Cholesterol-Triglyceride/5.0).
Body Mass Index
All subjects were weighed without clothing, other
than underwear, with the use of the same scale. Height was measured
with a special ruler affixed to the wall. Body mass index was
subsequently calculated as Weight in Kilograms/(Height in
Meters)2.
Statistical Considerations
Our primary end point was change in IMT over the
course of the study. This is an intent-to-treat analysis, under
which we consider IMT values for all patients initially randomized to
the enalapril group or the control group, regardless of subsequent
protocol violation. Our sample size of 98 NIDDM patients (48 enalapril,
50 control) is sufficient to detect a moderate effect size (that is,
difference in means of the 2 groups, divided by the common SD) of 0.5
with a statistical power of 0.7 or a large effect size of 0.85 with a
power >0.9 when treatment groups are compared, with a 2-sided
t statistic at conventional
level 0.05.
Summary statistics are presented as mean±SD. Differences between the 2 groups at each observation period were assessed with ANOVA; within- and between-group comparisons across the baseline and follow-up recordings were made with repeated-measures ANOVA. Best subsets linear regression18 was used to determine the effect of ACE treatment along with other potential covariates or predictors (demographics, baseline clinical data) on annual IM thickening and annual change in vascular lumen diameters. In this regard, we performed separate regression analyses for left and right carotid arteries but found few differences of note; hence, we report here regression analyses performed on the IMT and diameter data averaged within each patient.
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Results |
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Clinical Characteristics
Four patients in the enalapril group and 3 patients in the control group were protocol violators. We here report an intent-to-treat analysis, whereby we evaluate all 48 patients initially randomized to the enalapril group and the 50 patients initially randomized to the control group.
With regard to baseline characteristics, the
enalapril-treated and control groups were well balanced with regard to
age, sex, body mass index, prevalence of smoking, proteinuria,
hypertension, hyperlipidemia, family history of an
ischemic event (coronary artery disease,
arteriosclerosis obliterans, or stroke), or
medications received (Ca2+ channel blocker,
insulin, sulfonylurea, acarbose). No patient took metformin medication.
Summary values are given in
Table 1.
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Atherosclerotic Parameters
Using repeated-measures ANOVA with 1 grouping factor
(treatment group), we found no statistically significant differences
between the enalapril-treated and control groups in any of the
atherosclerotic parameters (systolic or
diastolic blood pressures, serum glucose,
HbA1c, total cholesterol,
triglyceride, HDL cholesterol, or LDL
cholesterol) over the baseline and follow-up measurements.
Using 1-way repeated-measures ANOVA within each treatment group, we
found 3 nominally significant time trends in atherosclerotic
parameters: (1) a linear trend in serum glucose levels in
the control group (F1,49=5.14,
P=0.028); (2) a quadratic trend
in HDL cholesterol in the control group
(F1,49=4.24,
P=0.045); and (3) a decrease in
systolic blood pressure in the enalapril-treated group at years
1 and 2 relative to baseline (F1,47=13.95,
P<0.0005). Summary statistics
are given in
Table 2.
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Carotid Ultrasonography Measurements
All carotid ultrasonography measurements were made
solely by 1 investigator (N.H.) to eliminate interobserver variability.
Intraday and interday reproducibility values of the investigator were
quite acceptable: the intraday coefficients of variation of IMT and
vascular lumen diameter of common carotid arteries were 2.7% and
2.1%, respectively, and the interday coefficients of variation of IMT
and vascular lumen diameter were 6.1% and 5.1%,
respectively.
Ninety-eight common carotid arteries, for both the right and
left arteries of each patient, were evaluated in this study (the
enalapril-treated group comprised 48 patients, and the control group
comprised 50 patients)
(Table 3). Annual IM thickening measurements of the
right and left common carotid arteries were 0.01±0.02 and
0.01±0.02 mm/y in the enalapril-treated group and 0.02±0.03 and
0.02±0.02 mm/y in the control group, respectively. From
regression analysis, annual IM thickening was found to be
predicted by enalapril use, sex, and insulin use
(F3,94=3.86,
P=0.012). When we controlled
for these other variables, enalapril use reduced annual IM
thickening of right and left common carotid arteries by
0.01±0.004 mm/y relative to the control group over the course of
this study. Annual proportional (relative) IM thickening measurements
of the right and left common carotid arteries were 2.2±3.2%/y and
1.3±2.2%/y in the enalapril-treated group and 3.7±4.1%/y and
2.9±3.0%/y in the control group, respectively. From regression
analysis, annual proportional IM thickening was found to be
predicted by enalapril use, sex, and insulin use
(F3,94=3.88,
P=0.012). When we controlled
for these other variables, enalapril use reduced annual
proportional IM thickening of right and left common carotid arteries by
1.3±0.6%/y relative to the control group. In these regressions,
insulin use was associated with increased IM thickening relative to
nonuse, and men had increased thickening relative to women. Annual
changes in vascular lumen diameter of the right and left common carotid
arteries were -0.08±0.28 and 0.00±0.26 mm/y in the
enalapril-treated group and 0.01±0.28 and 0.01±0.35 mm/y in the
control group, respectively. Regression analysis revealed that
annual changes in vascular lumen diameter were significantly related to
insulin use and acarbose use (F2,95=6.54,
P=0.002). Annual proportional
changes in vascular lumen diameter of the right and left common carotid
arteries were -1.0±4.2%/y and 0.3±4.5%/y in the enalapril-treated
group and 0.5±4.7%/y and 0.8±6.9%/y in the control group,
respectively. Again, annual proportional changes in vascular lumen
diameter were significantly related to insulin use and acarbose use
(F2,95=6.27,
P=0.003). In these regressions,
insulin use was associated with smaller (reduced) changes in vascular
lumen diameter relative to nonuse, whereas acarbose use was associated
with larger (increased) changes in vascular lumen diameter relative to
nonuse.
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Discussion |
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An increase of IMT of the common carotid artery is related to increased prevalence of myocardial infarction, angina, cerebrovascular disease, and peripheral vascular disease19 20 and is also associated with an increased risk of stroke and myocardial infarction.21 22 Previous studies have suggested that DM2 23 and insulin24 are related to increased stiffness of the arterial wall in humans. DM and mean fasting glucose level have been found to be positively associated with increased IMT of the common carotid artery but not IMT of the internal carotid artery. This pattern is different from hypercholesterolemia, which is related to plaque in the internal carotid arteries.4 DM is one of the most important risk factors for coronary artery disease, arteriosclerosis obliterans, and stroke.1 Many studies are focused on the prevention of coronary artery disease, arteriosclerosis obliterans, and stroke modulating IM thickening and plaques.12 13 25 Touboul et al26 reported that the risk of brain infarction increased continuously with increasing IMT of the common carotid artery. Recently, the HOPE Study14 showed that treatment with ramipril, an ACE inhibitor, reduced the rates of death, myocardial infarction, stroke, coronary revascularization, cardiac arrest, and heart failure as well as the risk of complications related to diabetes and of diabetes itself. Few other interventional studies had been undertaken aimed at the prevention of the atherosclerosis process in DM patients. In the present study we focused on NIDDM patients in the setting of a randomized clinical trial and found that, over time, IM thickening in these patients could be predicted by enalapril use, sex, and insulin use.
Ang II receptors, ACE,27 and angiotensinogen messenger RNA28 have been identified as humoral factors in the vascular wall in rats, and several lines of evidence have supported the role of a local renin-angiotensin system in the pathogenesis of neointima formation induced by vascular injury in rats.6 ACE inhibitors and Ang II receptor antagonists have been reported to prevent vascular SMC migration and growth, neointima formation, and accumulation of cholesterol in balloon injury models of rats and rabbits.6 7 8 In 1 study long-term treatment with ACE inhibitors reduced myointimal thickening induced by balloon injury in rat carotid artery or aorta.6 Hosoi et al10 showed that ACE insertion/deletion polymorphism is a genetic factor that may predict the progression of carotid atherosclerosis in NIDDM patients. Our results support the findings of these previous studies and suggest that long-term treatment with an ACE inhibitor (enalapril) slows progressive IM thickening of the common carotid artery in NIDDM patients.
Ultrasound methods that quantify the size of atherosclerotic lesions and arterial wall thickness are now commonly used in longitudinal studies of the time course of atherosclerosis. These measurements are dependent on high-resolution B-mode ultrasonography, a method that presents the arterial wall as a double-line pattern. Previous studies29 30 have reported a significant correlation between atherosclerotic changes and IMT. Persson et al30 showed that IMT values measured ultrasonographically and microscopically were closely correlated (r=0.82, P<0.001), with IMT determined by light microscopy consistently smaller than that determined by ultrasonography (mean difference, 0.14 mm). They attributed the difference between ultrasound- and light microscopy–determined IMT to shrinkage of soft tissues during histological preparations. We have relied solely on ultrasound measurements for outcome analyses in the present study; in this regard, we note that any systematic bias in ultrasound measurements would be of little consequence because our primary end point relates to changes in vessel sizes over time rather than absolute magnitudes.
IMT and vascular lumen diameter of the same macrovascular artery will vary together under conditions of high and low blood pressure. Under high blood pressure, macrovasculatures are distended and have a strong wall tension, making IMT thin and IM thickening faster. Conversely, under low blood pressure, macrovasculatures are constricted and have a low wall tension, making IMT wide and IM thickening slower. Enalapril, the ACE inhibitor used in the present trial, acts as a vasodilator of microvessels, reduces blood pressure, and decreases hemorheologic stress and vascular wall tension. Previous studies12 13 that have investigated ACE inhibitor efficacy for IMT of common carotid arteries in hypertensive patients could not definitively establish therapeutic efficacy. However, the observation periods of these studies ranged from 6 to 9 months, in contrast to the planned 24-month observation period in our trial. These previous studies reported mean reductions in blood pressure between baseline and follow-up measurements. In our trial systolic blood pressures decreased on average by 4.8 mm Hg during the first year and were maintained at the same level during the second year in the enalapril-treated group. This decreased systolic blood pressure during the first period may slightly constrict the common carotid artery during the same period and may transiently increase the apparent IMT, which may in turn decrease the wall tension and eventually slow the rate of IM thickening. From these various findings, we conclude that a minimum 2-year observation period should be incorporated into any future trials that evaluate therapeutic regimens on IMT to preclude possible early (up to 1 year) confounding of transient or apparent effects due to decreased systolic blood pressures. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE) trial, a substudy of the HOPE Study, has examined the effect of ramipril on IM thickening with 4 years of follow-up in 732 patients with cardiovascular disease or with diabetes and additional risk factors.25 In their study annual IM thickening was 0.0217 mm/y in the placebo group and 0.0137 mm/y in the ramipril (10 mg/d) group (P=0.033).
The Asymptomatic Carotid Artery Progression Study research group has estimated annual IM thickening of common carotid arteries as 0.006 mm/y in patients with coronary risk factors.31 In comparison, Handa et al29 estimated annual IM thickening of common carotid arteries as 0.008 mm/y in healthy Japanese subjects. Recently, Yamasaki et al32 estimated annual IM thickening of carotid arteries as 0.04 mm/y in Japanese NIDDM patients. Annual IM thickening of carotid arteries was positively related with the initial IMT or HbA1c in their study. In the present study annual IM thickening values of the right and left common carotid arteries were 0.02±0.03 and 0.02±0.02 mm/y in the control group of NIDDM patients. The faster annual IM thickening of carotid arteries in the aforementioned studies may reflect the characteristic differences in the study population compared with the present study. Patients in the aforementioned studies had higher HbA1c and older age than those in the present study. Nevertheless, in the present study annual IM thickening values of the right and left common carotid arteries were reduced to 0.01±0.02 and 0.01±0.02 mm/y in the enalapril-treated group, respectively. Thus, long-term treatment with enalapril can slow progressive IM thickening of common carotid arteries.
The magnitude of change in vascular lumen diameters of common carotid arteries over the course of our study was modest. This may be attributable to our exclusion of atherosclerotic lesions of >1.0 mm in IMT from consideration. Glagov et al33 showed that, before stenosis is >40%, the actual lumen area seems to remain independent of the plaque area, reflecting the corresponding increase in arterial size. In our study we measured IMT and vascular lumen diameter in common carotid arteries that showed no plaque (0% stenosis). This should yield precise estimation of early changes of IMT in NIDDM.
Potential limitations of this study might include the limited sample size and lack of placebo control. Our sample size of 98 is modest in comparison to enrollments in large multicenter trials; however, our sample size calculation (mentioned previously) does establish that the trial was sufficiently powered to find moderate effect sizes, if they indeed existed. We recognize that our control group was not given a placebo. However, given the duration of our study (minimum of 2 years), whatever placebo effect might be anticipated at the outset of the trial would surely be dissipated by the end. Additionally, our end point—IM thickening—is clearly objective and would reasonably be totally insensitive to any placebo effect. Furthermore, patients were randomly assigned to treatment arms, and our evaluators remained blinded to treatment assignment; therefore, we would argue that no bias was introduced by the failure to dispense a placebo.
In summary, we used enalapril to evaluate the effect of an ACE inhibitor. From our findings, we conclude that enalapril is effective in slowing progressive IM thickening in NIDDM patients. This slowing effect of enalapril may be the mechanism whereby an ACE inhibitor reduced the incidence of cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in the HOPE Study.14 We believe that this is likely to be a class effect, since previous studies have shown that many other ACE inhibitors (cilazapril, perindopril, captopril, and fosinopril) also prevent neointima formation and inhibit the development of atherosclerosis in hypercholesterolemia6 7 8 ; ramipril also slows progressive IM thickening of the carotid arteries in patients with cardiovascular disease or with diabetes and additional risk factors.25 However, in the Quinapril Ischemic Event Trial (QUIET), quinapril did not reduce progression of coronary atherosclerosis, a new stenosis development, in patients with coronary artery disease in the absence of congestive heart failure and/or hyperlipidemia (the prevalence of hypertension was 47%, and that of diabetes [type 2] was 16%).34 Previous studies have also shown that an angiotensin subtype 1 receptor antagonist markedly suppressed myointimal thickening and reduced neointima formation in an experimental model.7 35 However, the effect of Ang II receptor antagonists remains controversial; further studies will be necessary to establish whether Ang II receptor antagonists have any clinically significant antiatherogenic effect in humans.
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Acknowledgments |
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This study was supported by the regional sanatorium grant (1997) from the Japanese government.
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Footnotes |
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Reprint requests to Naohisa Hosomi, MD, PhD, Kagawa Medical University, Second Department of Internal Medicine, 1750-1 Ikenobe, Miki-cho, Kagawa 761-0793, Japan.
Received August 9, 2000; revision received March 3, 2001; accepted March 14, 2001.
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