© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Cholesterol-Lowering Treatment Is Associated With Improvement in Coronary Vascular Remodeling and Endothelial Function in Patients With Normal or Mildly Diseased Coronary Arteries
From the Center for Coronary Physiology and Imaging, The Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn.
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Abstract |
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Abstract— Coronary vascular remodeling and altered endothelial function have been described in the early stages of native atherosclerosis. The purpose of this study was to evaluate the association between cholesterol-lowering therapy and coronary vascular remodeling and endothelial function in patients with normal or mildly diseases coronary arteries. Patients (N=101) with normal or mildly diseased coronary arteries by coronary angiography underwent intravascular ultrasound examination of the left anterior descending coronary artery. Vessel and lumen area, atherosclerotic plaque area, and plaque morphology were evaluated. Vascular reactivity was examined with the use of intracoronary adenosine, acetylcholine, and nitroglycerin. Patients were divided into 3 groups based on the total cholesterol levels: group 1 (n=25), patients with a history of hypercholesterolemia adequately treated (total cholesterol <240 mg/dL); group 2 (n=26), patients with hypercholesterolemia not adequately controlled (total cholesterol
240 mg/dL); and group 3
(n=50), patients without hypercholesterolemia.
Vessel area and lumen area were significantly greater in groups 1 and 3
than in group 2 (for respective values in groups 1, 2, and 3: vessel
area 11.9±0.5, 10.6±0.4, and 11.8±0.4 mm2, both
P<0.05; lumen area 8.3±0.4, 6.9±0.3, and
8.9±0.3 mm2, both P<0.01). However,
plaque areas in groups 1 and 2 were similar. Furthermore,
acetylcholine-induced percent increases in coronary blood flow
were significantly greater in groups 1 and 3 than in group 2 (for
respective values in groups 1, 2, and 3: 70.5±20.1%, 22.8±13.7%,
and 68.6±14.8%, both P<0.05).
Cholesterol-lowering treatment is associated with an
improvement in coronary lumen area that results not from a
decrease in plaque area but from an increase in vessel area, reflecting
vascular remodeling. Additionally, this adaptive process may occur in
association with an improvement of
endothelium-dependent vasodilation of the resistance
coronary artery.
Key Words: remodeling • hypercholesterolemia • cholesterol • endothelium • ultrasonics
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Introduction |
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Using histopathological techniques, Glagov et al1 examined the effects of plaque development on vessel and lumen area of the left main coronary artery and demonstrated that adaptive enlargement of the wall of diseased arterial segments occurs to compensate for the accumulation of atherosclerotic plaque. Several studies have reproduced these results in vivo by using epicardial or intravascular ultrasound techniques.2 3 4 5 6 These studies have shown that the increase in plaque area is apparently uniformly accompanied by an increase in total vessel area; in this way, luminal dimensions are preserved until the progressive accumulation of plaque exceeds the ability of the vessel to compensate.1 Thus, compensatory enlargement, reflecting vascular remodeling, is now recognized as an important adaptive process in early atherosclerosis.
Hypercholesterolemia is recognized as a risk factor for ischemic heart disease and coronary mortality.7 8 9 Several trials have demonstrated that cholesterol-lowering therapy markedly reduces cardiovascular mortality.10 11 12 It has been suggested that the reduction in coronary events seen in the angiographic trials is greater than would be expected for the degree of angiographic improvement induced by cholesterol lowering. Plaque stabilization that is due to a decrease in the lipid content of the lesions, improved endothelial function, and the reduction of thrombogenic risk are 3 mechanisms that could partly account for the reduction in coronary events with cholesterol lowering.13 14 15 16 Another associated mechanism may be a beneficial effect on coronary vascular remodeling. However, the association between cholesterol lowering and coronary vascular remodeling and endothelial function in humans is not fully defined.
Thus, the present study was designed to assess the association between hypercholesterolemia and cholesterol-lowering therapy on coronary vascular remodeling and endothelial function in humans.
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Methods |
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Study Population
Patients (N=101) who had been referred for cardiac catheterization to exclude coronary artery disease were prospectively studied. Patients with an obvious history of variant angina, cardiomyopathy, previous myocardial infarction, previous coronary artery bypass graft, or coronary intervention were excluded from the present study. Long-acting nitrates or calcium channel–blocking agents were withheld for 36 to 48 hours before the study. The study was approved by the Mayo Clinic Institutional Review Board, and all patients agreed to participate in the study.
Patients were included in the present study if they had the following: (1) angiographically smooth arteries, (2) mild irregularities with no coronary artery lesion with >30% diameter stenosis by visual assessment in any major epicardial vessel, and (3) proximal coronary arteries >2.0 mm in diameter.
The 101 patients of the present study were divided into 3 groups according to their history of hypercholesterolemia and their total serum cholesterol level at the time of the study. Group 1 consisted of 25 patients who had been previously diagnosed with hypercholesterolemia and had reduced their total serum cholesterol levels to <240 mg/dL. Group 2 consisted of 26 patients who had been previously diagnosed with hypercholesterolemia and had failed to reduce their total serum cholesterol levels to <240 mg/dL. Patients who had not been diagnosed with hypercholesterolemia and were first diagnosed with hypercholesterolemia at the time of the study were also included in group 2. Group 3 consisted of 50 patients without hypercholesterolemia.
Definition of Hypercholesterolemia
A total cholesterol level of 240 mg/dL was
used for the definition of
hypercholesterolemia. Blood specimens from the
subjects were analyzed in a Mayo Clinic medical laboratory.
Venous blood specimens were obtained after an overnight 12-hour fast.
Serum lipids were measured with use of the following techniques:
cholesterol and triglycerides were determined
by enzymatic methods, HDL cholesterol was isolated by
dextran precipitation, and LDL cholesterol was calculated
with use of the Friedewald formula.17
Study Protocol
Diagnostic coronary angiography was
performed by using a 6F Judkins catheter with a standard femoral
percutaneous approach. Heparin (2500 U) was
administered at the beginning of the procedure. Nonionic contrast
material was used for all patients. No nitroglycerin
was given before the diagnostic procedure.
Vasomotor responses to acetylcholine and adenosine were studied accordingly to a previously reported protocol.18 19 20 After control coronary angiograms had been obtained, a 0.014-in Doppler guidewire (Endosonics) was introduced through an 8F guiding catheter into the left anterior descending coronary artery (LAD). Once baseline flow velocity data were obtained at the position (when a stable Doppler signal was obtained), a bolus of intracoronary adenosine (24 to 36 µg, from a solution of 6 mg adenosine in 1 L of saline) was administered. Then selective intracoronary infusion of increasing concentrations of acetylcholine (10-6, 10-5, and 10-4 mol/L) was performed for a total duration of 3 minutes through a 2.2F Ultrafuse coronary infusion catheter (SciMed Life System).21 Symptoms, hemodynamic data, ECG, and Doppler velocities were recorded at the end of each infusion. Before the end of each dose of acetylcholine, a selective angiography was repeated. After infusions of acetylcholine, 300 µg of intracoronary nitroglycerin was given, and angiography was repeated within 2 minutes by using the same projection as the baseline.
Intravascular Ultrasound Examination
One of 2 intracoronary ultrasound systems (Endosonic and
Hewlett-Packard) was used in the present study. Details of these
systems have been described elsewhere.22 23 The
intracoronary ultrasound catheters were inserted through the 8F
guiding catheter and placed into the middle portion of the LAD over a
0.014-in high-torque floppy guidewire (Advanced
Cardiovascular Systems). Images were obtained after
administration of intracoronary nitroglycerin.
All images were performed by manual pullback from the second diagonal
coronary artery to the bifurcation of the LAD with the
circumflex artery, and segments were visualized. These selected vessel
segments were visually divided to equal 
4 or 5 segments, and images
were obtained accordingly. After optimization of the ultrasound image,
continuous real-time images were recorded on 0.5-in videotape. Four
or 5 segments of the LAD were identified on the videotape
recording of the ultrasound images, and the exact position of
the ultrasound catheter in relation to the artery was recorded on
cine film at each position. The location of the catheter as seen on the
cine film at each segment position was used to correlate the identified
ultrasound imaging with the angiographic segment.
Quantitative Coronary Angiography
Analysis of artery diameter from the cine films was
performed with a modification of the technique previously
described.18 24 25 A diastolic still frame at
each infusion (baseline, saline solution, 3x acetylcholine, and
nitroglycerin) was selected from the cine film. The
different segments of the artery selected at the time of
intracoronary ultrasound imaging were identified on the
radiograph. By use of the computer-interactive digitizing system, the
outline of the contrast material within the lumen was digitized at each
specific region of interest identified. The absolute diameter of the
vessel lumen perpendicular to the long axis of the artery at the
selected specific points of the artery was measured by using the guide
catheter as the calibration standard. These measurements were taken by
observers without knowledge of the ultrasound findings.
Assessment of Coronary Blood Flow
Doppler flow velocity spectra were analyzed on-line
to determine time-averaged peak velocity. Coronary flow reserve
was calculated as the ratio of hyperemic to basal average peak
velocity of the distal vessel. Volumetric coronary blood flow
(CBF) was determined from the following relation: CBF=cross-sectional
areaxaverage peak velocityx0.5.26
Ultrasound Image Analysis
An off-line computer-interactive analysis system was
used to digitize the intracoronary ultrasound video images onto
a 256x256-bit matrix. Standard calibration markers directly from the
ultrasound image were used for calibration of absolute measurements.
Measurements of area stenosis and minimal lumen diameter were
made of the most severely stenosed region at each specific segment of
the artery that had been previously identified. With computer
planimetry, the specific segment was assessed quantitatively. The
external elastic membrane cross-sectional area, which
represents the area within the border between the hypoechoic
media and echoreflective adventitia, was a measure of total
arterial cross-sectional area (vessel area, Figure 1
). Because medial thickness cannot be
measured accurately by intravascular ultrasound, plaque plus medial
cross-sectional area (plaque area), which was calculated as external
elastic membrane cross-sectional area (vessel area) minus lumen
cross-sectional area (lumen area), was used as a measure of plaque
mass.22 27 Percent area stenosis was calculated as
the ratio of plaque plus media to external elastic membrane
cross-sectional area. Morphological plaque features were classified
according to the following definitions by consensus: Segments that had
a concentric prominent leading-edge echo and a widened subintimal
echolucent zone (with a combined thickness <0.3 mm) were
classified as normal. Soft plaque was less dense than the reference
adventitia. Fibrous plaque was composed of thickened dense echoes
involving the intimal leading edge with a homogeneous
echodensity equal to that seen for the adventitia. Hard plaque was more
dense than the reference adventitia and had no acoustic shadowing.
Calcific tissue produced bright echoes with acoustic shadowing. In
segments with a calcium arc >90°, the external elastic lamina was
not traced because of potential inaccuracy due to the shadowing, and
these segments were excluded from further analysis. These
measurements were performed by observers without knowledge of the
results of the endothelial function or the
cholesterol levels.
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Interobserver and Intraobserver Variability
Two ultrasound sites from 10% of the patients studied were
randomly selected and measured by the same observer on 2 separate
occasions and also by a second observer. These measurements were then
used to evaluate intraobserver and interobserver variability. These
were expressed as linear regression between the 2 observations and as
percent error, derived as the absolute difference between
observations.
Statistical Analysis
Continuous variables are presented as mean±1 SE.
Differences in groups among baseline variables were tested by 1-way
ANOVA. Discrete variables are presented as percentages. The
Pearson 
2 test was used to determine
significant baseline differences. Appropriate transformations for
vessel area, lumen area, and percent change in CBF were used to
normalize the response distributions. Significant treatment differences
in vessel area, lumen area, and percent change in CBF were adjusted for
age, sex, and hypertension. To account for multiple observations of
lumen and vessel area per subject, generalized estimating equations
with exchangeable correlation structure were used to model the marginal
distribution of these variables. Treatment parameters
were then used for significance by using an approximation to the
standard normal distribution with empirical standard errors. Treatment
differences in percent change in CBF were determined with an F
test.28
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Results |
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Segments (N=456) derived from the 101 patients with normal and mildly diseased coronary arteries were initially selected. Eleven angulated segments, 6 segments of bifurcated lesions, and 30 segments with a calcium arc >90° were excluded. Twelve segments with technical problems of video images were also excluded from analysis. Thus, a total of 397 segments from the 101 patients were evaluated.
Patient Characteristics
Sex distribution, age, and body surface area were comparable in
the 3 groups. With regard to other coronary risk factors, there
were no significant differences among the study group (Table 1).
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Serum Lipids
Group 1 consisted of patients with a history of
hypercholesterolemia that was adequately
treated; their mean total cholesterol level was 203.2±4.8
mg/dL. The duration of cholesterol-lowering therapy was
27±21.0 months. Group 2 consisted of patients with
hypercholesterolemia that was not adequately
controlled; their mean total cholesterol level was
273.3±4.4 mg/dL. Group 3 consisted of patients without
hypercholesterolemia; their mean total
cholesterol level was 193.2±5.1 mg/dL. Total serum
cholesterol and LDL cholesterol were
significantly (P<0.001) elevated in group 2 compared with
groups 1 and 3. HDL cholesterol was normal in all 3 groups
and did not differ significantly between them. Triglyceride
levels were significantly (P<0.01) elevated in group 2
compared with group 3 (Table 1
).
Intravascular Ultrasound Data
The dimensions of vessel area, lumen area, and plaque area of the
3 groups are shown in Figure 2. Plaque
areas in groups 1 and 2 were similar and significantly
(P<0.05 and P<0.01, respectively) larger than
plaque areas in group 3: 3.6±0.3 mm2 (group
1), 3.7±0.2 mm2 (group 2), and
2.9±0.2 mm2 (group 3). However, lumen areas
in the groups with total cholesterol <240 mg/dL (groups 1
and 3) were similar and significantly (P<0.01) larger than
lumen areas in group 2: 8.3±0.4 mm2 (group
1), 6.9±0.3 mm2 (group 2), and
8.9±0.3 mm2 (group 3). In addition, vessel
areas in groups 1 and 3 were similar and significantly
(P<0.05) larger than vessel areas in group 2:
11.9±0.5 mm2 (group 1), 10.6±0.4
mm2 (group 2), and 11.8±0.4
mm2 (group 3). This significant difference
persisted when measurements were adjusted for sex and indexed to body
surface area: vessel area 6.06±0.2 mm/m2
(group 1) and 6.38±0.2 mm/m2 (group 3)
versus 5.43±0.2 mm/m2 (group 2),
P<0.05 and P<0.01, respectively; lumen area
4.27±0.2 mm/m2 (group 1) and 4.82±0.1
mm/m2 (group 3) versus 3.53±0.1
mm/m2 (group 2), P<0.01 and
P<0.001, respectively. Furthermore, to adjust for the
nonsignificant differences between the various groups in the incidence
of diabetes, analyses were also performed after excluding
diabetic patients, and these differences remained significant: vessel
area 11.9±0.5 mm2 (group 1), 10.5±0.4
mm2 (group 2), and 11.9±0.4
mm2 (group 3), P<0.05 and
P<0.01 for groups 1 and 3 versus group 2; lumen area
8.3±0.4 mm2 (group 1), 6.9±0.3
mm2 (group 2), and 9.0±0.3
mm2 (group 3), P<0.001 for groups 1
and 3 versus group 2.
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P<0.01 vs group 2; 
P<0.05 vs group
3; and §P<0.01 vs group 3.
The correlation between vessel area and plaque area is shown in Figure 3. Vessel area significantly increases
with plaque area in all 3 groups. Vessel area in groups 1, 2, and 3
increased by 1.24, 1.08, and 1.35 mm2,
respectively, for every 1-mm2 increase in plaque
area, suggesting that the vessel enlarges in response to plaque
accumulation (r=0.63, P<0.0001;
r=0.68, P<0.0001; and r=0.61,
P<0.0001, respectively).
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Percent area stenosis, maximal thickness of plaque, and plaque
composition are shown in Table 2. Percent
area stenosis and maximal plaque thickness in both the
hypercholesterolemic groups (1 and 2) were similar and
significantly greater than those values in group 3, which had no
history of hypercholesterolemia
(P<0.01 and P<0.001, respectively). Groups 1
and 2 had a significantly higher percentage in composition of hard
plaque and calcified plaque than group 3 (P<0.01 and
P<0.05, respectively). However, groups 1 and 2 did not
differ in any type of plaque. Even after adjustment with all other
cardiovascular risk factors, the association between
hypercholesterolemia,
cholesterol-lowering therapy, and coronary artery
remodeling remained significant.
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The left main coronary artery vessels were used as the referenced vessels for the 3 groups, and there were no significant differences between the 3 groups (20.6±1.2 mm2 in group 1, 23.7±1.3 mm2 in group 2, and 22.6±1.3 mm2 in group 3).
Changes in CBF
Baseline CBF did not differ among groups 1, 2, and 3 (51.4±6.8,
51.5±7.1, and 53.6±3.7 mL/min, respectively). With regard to
calculated coronary flow reserve examined when
adenosine was used, there was no significant difference between
the 3 groups. Intracoronary acetylcholine induced similar
increases in CBF in both groups with total cholesterol
<240 mg/dL (groups 1 and 3); the increases were significantly greater
than those in group 2 (P<0.05). This was associated with
similar changes in coronary artery diameters. The percent
increases in CBF induced by nitroglycerin were similar
between the groups (Table 2).
The interobserver variability was 0.4±2.4% and 1.06± 4.3% for the coronary diameter and area measurements, respectively, and the intraobserver variability was 0.8±1.9% and 1.5±3.3% for the coronary diameter and area measurements, respectively.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study demonstrates that coronary vascular remodeling and coronary endothelial function are impaired in patients with hypercholesterolemia. Moreover, cholesterol-lowering treatment was associated with an increase in lumen area that was due to an increase in vessel area rather than a decrease in plaque area, reflecting vascular remodeling. These changes were associated with improvement in endothelial function.
Patients with hypercholesterolemia have an early and accelerated course of coronary atherosclerosis.29 30 Coronary angiography, which uses contrast medium to visualize the coronary artery lumen, is limited to the measurement of a reduction in lumen diameter rather than the extent of atherosclerosis. However, intracoronary ultrasound provides the opportunity to identify early atherosclerotic change in the coronary artery wall during the process of atherosclerosis.31
Coronary remodeling may be defined as any change in artery size. It may be considered favorable (adaptive or outward expansion) or unfavorable (pathological or inward shrinkage).32 Thus, impaired or unfavorable coronary artery remodeling may contribute to the early and accelerated course of coronary atherosclerosis and may lead to greater luminal stenosis for the same amount of atherosclerotic plaque in patients with hypercholesterolemia. Plaque stabilization, improved endothelial function, and the reduction of thrombogenic risk are 3 mechanisms that could partly account for the reduction in coronary events with cholesterol-lowering therapy.14 15 16 Another mechanism may be the improvement of impaired coronary artery remodeling. Clarkson et al33 have suggested that the failure of adaptive remodeling may be an important factor in the development of significant atherosclerotic lesions.
Our results are consistent with previous studies that demonstrated impairment of coronary endothelial function in patients with hypercholesterolemia.34 35 Moreover, cholesterol-lowering therapy was associated with an improvement in endothelial function in these patients.15 There were no significant differences between the groups in coronary artery diameter changes in response to acetylcholine, indicating that the response was mainly at the level of the resistance vessels. The CBF responses to the endothelium-independent vasodilator nitroglycerin and adenosine did not differ among the 3 groups. Thus, these findings suggest that an impairment of endothelium-dependent vasodilatation of the resistance coronary artery coincides with structural changes in the coronary arteries in patients with hypercholesterolemia and that normalization of these alterations is associated with effective cholesterol-lowering treatment.
Mechanisms of Favorable Coronary Remodeling
The mechanism of compensatory enlargement is not completely
elucidated, but a number of hypotheses have been suggested, including
bulging of the vessel wall because of degradation of the underlying
media and adventitia in response to the development of
plaque36 37 38 and/or intimal thickening39 and
arterial dilatation initiated by increased shear stress
secondary to increased velocity of flow in stenotic
arteries.40 41 42 43 44 The small decreases in the lumen in
response to the development of plaque produce a large increase in shear
stress on the vessel wall.45 The artery normalizes the
shear stress by expanding to normal lumen size.41 46
Langille and O’Donnell42 have demonstrated that this is
probably an endothelium-dependent response to
coronary flow abnormalities. Shircore et al47 have
speculated that coronary artery remodeling might occur in
response to changes in CBF reserve. In addition, we have recently
demonstrated that experimental
hypercholesterolemia is characterized by
altered coronary endothelial function and
vascular structural changes, suggesting an association between the 2
processes.48 49 Thus, the present study suggests that
the improvement in the remodeling process in association with
cholesterol-lowering therapy occurs not by changes in
plaque area but rather by a combination of mechanisms that may affect
the vessel wall structure.
Study Limitations
The limitations of intracoronary ultrasound imaging and
Doppler flow velocity have been described in detail
elsewhere.50 51 The present study is a cross-sectional
study, and its findings may warrant confirmation through a prospective
study.
Clinical Implications
Previous studies have demonstrated an improvement in lumen as
detected by coronary angiography after cholesterol
lowering.52 53 The present study extends these
previous observations and demonstrates that the enlargement of the
lumen may be the result of vascular remodeling, resulting in an
increase in vessel area rather than a decrease in plaque area.
Previous investigators have demonstrated vascular remodeling in advanced coronary atherosclerosis. The present study focused on the early stage of coronary atherosclerosis and has demonstrated that even at this early stage of the disease, without significant luminal disease, there are significant functional and structural changes. Moreover, the present study suggests that lowering the cholesterol levels at an early stage of coronary atherosclerosis is associated with beneficial effects on coronary vascular function and structure.
Conclusions
A decrease in lumen area in patients with
hypercholesterolemia may result from an
attenuated compensatory enlargement of vessel area in response to an
increase in plaque area. The associated improvement in lumen area in
the cholesterol-lowering treatment group may result not
from a decrease in plaque area but from an increase in vessel area,
reflecting vascular remodeling. In addition, our results suggest that
impairment of endothelium-dependent vasodilatation at
the level of the resistance coronary artery in these patients
may be normalized with effective cholesterol-lowering
treatment. Therefore, this adaptive process in the epicardial
coronary artery may occur in association with an improvement of
endothelium-dependent vasodilation of the resistance
coronary artery.
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Acknowledgments |
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This study was supported by the Miami Heart Research Institute, the Bruce and Ruth Rappaport Vascular Biology Program, and the Mayo Foundation.
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Footnotes |
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Reprint requests to Amir Lerman, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Received August 10, 1999; accepted September 27, 1999.
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