(Circulation. 1995;92:2411-2418.)
© 1995 American Heart Association, Inc.
Articles |
Compensatory Vascular Changes of Remote Coronary Segments in Response to Lesion Progression as Observed by Sequential Angiography From a Controlled Clinical Trial
From the Atherosclerosis Research Unit, Division of Cardiology and the Statistical Consultation Research Center, Departments of Medicine (A.M.S., H.N.H.) and Preventive Medicine (W.J.M., S.P.A., H.N.H.), University of Southern California School of Medicine, Los Angeles; the Jet Propulsion Laboratory (A.M.S., R.H.S., P.L.L.), Pasadena, CA; and the Oklahoma Medical Research Foundation (P.A.).
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Local coronary artery enlargement to compensate for atherosclerotic plaques preserves the vessel lumen. The extent to which coronary segments remote from progressing lesions enlarge is unknown. This is clinically relevant since compensatory enlargement may be important in determining whether clinical complications result from progression of coronary artery disease (CAD). Additionally, compensatory change has implications for quantitative coronary angiographic (QCA) trials, since the effect of progression on diameter means may be mitigated by compensatory changes in remote coronary segments when QCA change is averaged over all lesions.
Methods and Results Serial QCA data from 78 subjects in the Monitored Atherosclerosis Regression Study were used to demonstrate compensatory changes in coronary segments remote from progressing or regressing lesions. Coronary segments were first classified as progressing (regressing) if percent diameter stenosis (PS) increased or decreased by >10 with a concurrent decrease or increase in minimum lumen diameter (MLD) of either >0.32 mm or >10% of the normal baseline reference diameter (DNORM). Segments not meeting these criteria were labeled stenosis stable. Stenosis-stable segments opposite progressing lesions showed increases in MLD (P=.0006), DNORM (P=.001), and average diameter (P=.001). On-trial apolipoprotein (apo) B, apo C-III, and blood pressure levels inversely correlated with these compensatory changes.
Conclusions Lesion progression in one coronary segment is associated with significant increases in segmental diameter of remote parts of the coronary tree. We hypothesize these increases to be vascular compensatory changes in response to progression of CAD. Vascular compensatory change is enhanced by LDL cholesterol and triglyceride-rich lipoprotein reduction and appears to be part of the treatment effect itself.
Key Words: coronary disease • apolipoproteins • angiography • cholesterol • lipoproteins • remodeling
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Local coronary artery enlargement to compensate for growing atherosclerotic plaques has been demonstrated with quantitative histology.1 2 During this chronic compensatory process, external coronary artery dimensions increase to preserve the vessel lumen area as intimal plaques grow. Recently, local compensatory coronary artery enlargement in response to obstructive atherosclerotic lesions has been demonstrated to occur in vivo in vessels lacking collateral formation.3 However, it is unknown whether coronary artery compensatory changes occur in segments remote from progressing lesions, which intrude into the vessel lumen. This is clinically relevant because collateral vessels are not angiographically visible and most likely are not functional until arterial occlusion is almost complete.4
In recent years, a number of clinical trials have assessed the benefits of lipid-lowering therapy on the progression of coronary atherosclerosis.5 Most observers report beneficial effects of lipid-lowering therapy on coronary artery lesions by demonstrating a reduction in progression and in some cases regression of lesions. However, the extent to which vascular compensation occurs in response to changes in coronary blood flow reserve in remote vessel segments has not been explored. Vascular compensatory change in remote vessel segments deserves attention since the absence of this process may be a major factor in determining whether clinical complications result from progression of coronary artery disease (CAD).
In this report, we use serial QCA data from the Monitored Atherosclerosis Regression Study (MARS) to demonstrate that in response to lesion progression, vascular compensatory change occurs in remote vessel segments. We first identified coronary artery segment progression or regression. Stenosis-stable segments were then classified by location relative to these changing segments. Our aim was to quantify luminal diameter changes in these stenosis-stable segments. We further demonstrate that the extent of vascular compensation is enhanced by reductions in the levels of apo B and triglyceride-rich lipoproteins.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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MARS Study Design
The MARS design has been described in detail previously.6 7 In brief, MARS was a randomized, double-blind, placebo-controlled coronary angiographic trial testing 80 mg per day lovastatin (L) versus placebo (P) in 270 subjects. Both treatment groups had identical targets for fat intake, <27% of calories as fat with daily cholesterol intake <250 mg. The study population included men and women 37 to 67 years of age (mean age, 58 years) with plasma total cholesterol 190 to 295 mg/dL (4.91 to 7.63 mmol/L) and CAD in two or more coronary artery segments with at least one segment narrowed by >50 PS (but <100 PS) and unaltered by percutaneous transluminal coronary angioplasty (PTCA).
Coronary Angiographic Procedures and
Measurements
Coronary arteriography was performed with the
percutaneous femoral technique in sufficient right
anterior oblique and left anterior oblique views to demonstrate all
lesions. After 2 years, follow-up arteriography exactly duplicated
the sequence of arteriographic projections, x-ray field, and
catheter size of the baseline arteriography. If
nitroglycerin was given during baseline arteriography,
it was administered at the same time point in the follow-up
procedure.
Baseline and 2-year angiograms were evaluated by automated QCA as previously described.6 7 Dual projectors were used for view matching and simultaneous digitization of baseline and 2-year film pairs. All analyses were performed with the operator blinded to treatment allocation. Film pairs were processed in tandem, and the frames were matched for orientation and degree of contrast filling. Arterial segments were defined from branch to branch. Each of the following measures was obtained in all processable arterial segments: (1) MLD, in millimeters, defined as the 3rd percentile of the distribution of diameters within each segment; (2) DNORM, in millimeters, defined as the 90th percentile of the distribution of diameters within each segment; (3) DAVE, in millimeters, defined as the average of all measured diameters within each segment; and (4) PS within each segment, defined as 100x(1-MLD/DNORM). Three sequential frames, principally exposed during end diastole, were digitized, measured, and averaged.8
Classification of Segments
Coronary artery segments were
classified as progressing
if PS increased >10 with a concurrent decrease in MLD of either >0.32
mm or >10% of the DNORM. Segments were classified as regressing if PS
decreased >10 with a concurrent increase in MLD of either >0.32 mm or
>10% of the DNORM. Both parameters had to change together
for a lesion to qualify as progressing or regressing. A PS change of 10
or greater and an MLD change of 0.32 mm or greater were chosen because
these values represent 2 SDs of changes in PS and MLD,
respectively, in short-term repeated angiography. Although MLD
change in the majority (82%) of progressing and regressing segments
was >0.32 mm, a change in MLD based on the DNORM was used for
classification of change in smaller vessels since all distal portions
and measurable branches were analyzed. Normal baseline
diameters of these smaller vessels were between 1.5 and 3.0 mm. An MLD
change equivalent to 10% of the normal baseline diameter
represents a PS change of 10. Use of dual criteria (ie, both PS
and MLD) for segmental change eliminated possible misclassification of
segment progression or regression owing solely to change in the
DNORM.
Segments not progressing or regressing according to the dual criteria noted above were labeled stenosis-stable segments. These stable segments were next subclassified as proximal, distal, adjacent, or opposite to progressing or regressing segments. By definition, proximal stable segments supplied blood to, and distal stable segments received blood from, a progressing or regressing segment. Adjacent stable segments were defined as branches of the larger coronary arteries, eg, a stenosis-stable segment in the diagonal artery would be classified as adjacent to a progressing segment of the left anterior descending coronary artery if the branch point was proximal to the progression; a stenosis-stable segment in the marginal artery would be classified as adjacent to the circumflex artery under the same circumstances. Likewise, circumflex stenosis-stable segments distal to the junction between the circumflex and marginal arteries would be classified as adjacent to a progressing segment in the marginal artery. Opposite stenosis-stable segments were on the opposite side of the coronary tree from progressing or regressing segments, eg, when a progressing or regressing segment was in the left anterior descending coronary artery or a branch of that artery, stenosis-stable segments in the right coronary artery and circumflex artery or branches of these arteries would be classified as opposite.
Classification of Subjects
Subjects with at least one
progressing segment and with all
remaining segments stable were classified as progressors. Subjects with
at least one regressing segment and with all remaining segments stable
were classified as regressors. Subjects with both progressing and
regressing segments (defined by dual criteria) were excluded to
simplify these analyses because interpretation of remote
segmental compensatory change owing to both progressing and regressing
lesions would be difficult. These analyses, therefore,
represent the relation between sole progression or sole
regression on remote coronary artery segmental change.
Selection of Subjects
Seventy-eight of 247 MARS subjects with
baseline and 2-year
angiograms evaluated by QCA were identified as progressors (n=59) or
regressors (n=19). One hundred sixty-nine subjects were excluded
for the following reasons: both progressing and regressing segments in
the same subject (n=32), no progressing or regressing segments by dual
criteria (n=40), patent bypass grafts (n=45), angioplasty
between
baseline and 2-year angiograms (n=22), nitroglycerin
administered at one angiogram (n=19), and miscellaneous technical
problems such as unknown catheter size and angiographic views that were
not well matched (n=11).
Statistical Analyses
Comparisons within and among segments
were conducted using the
statistical method of Rosner.9 This method incorporates
the intraclass correlation between segments within subjects into the
regression model to allow hypothesis testing of such dependent data.
QCA measures (ie, MLD, DAVE, DNORM, PS) were analyzed
separately at baseline and for change (2-year value minus baseline
value) in progressors and regressors. These changes were tested against
zero across all stenosis-stable segments and within each
stable segment category (proximal, distal, adjacent, and opposite);
this analysis was performed for lovastatin and
placebo treatment groups combined. Treatment group differences in the
QCA changes were also tested. QCA measures in
stenosis-stable segments at baseline as well as changes
from baseline were tested for equality between progressors and
regressors.
Univariate and stepwise regression analyses were performed to determine significant clinical, lipid, lipoprotein, and apo correlates of change in MLD, DAVE, DNORM, and PS in opposite stable segments. To adjust for the possible confounding effects of the actual degree of angiographic change in the progressing or regressing segment, changes in MLD and PS of the changing segment were forced in as model covariates. Competing variables in the stepwise analysis were on-trial total cholesterol; LDL cholesterol; HDL cholesterol; triglycerides; apos B, A-I, E, C-III in whole serum, C-III in heparin supernate (HDL associated apo C-III), and C-III in heparin precipitate (LDL-VLDL–associated apo C-III); systolic and diastolic BPs; pulse rate; subject classification (progressor, 1; regressor, 0); and treatment group (L, 1; P, 0).
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Comparison Between and Within Segments
Fifty-nine progressors (25 L, 34 P) had 98 progressing segments; 36 had 1 progressing segment, 14 had 2 progressing segments, and 9 had multiple progressing segments. These 59 progressors had 441 stable segments: 78 proximal, 59 distal, 69 adjacent, and 235 opposite, to progressing segments. Nineteen regressors (12 L, 7 P) had 27 regressing segments; 12 had 1 regressing segment, and 7 had multiple regressing segments. These 19 regressors had 144 stable segments: 21 proximal, 11 distal, 12 adjacent, and 100 opposite, to regressing segments.
Table 1
summarizes baseline values for
progressing and
regressing segments and stable segments. Stable segments were
moderately stenotic at baseline and not significantly different
between progressors and regressors. On the other hand, regressing
segments were significantly more stenotic at baseline than
progressing segments (59.03 versus 36.95, P<.0001). The MLD
at baseline of regressing segments was significantly less than that of
progressing segments (1.08 versus 1.88 mm, P<.0001). DAVE
and DNORM were also smaller in regressing segments but were not
significantly different.
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Table 2 summarizes changes from
baseline within and
between groups for progressing and regressing segments. In progressing
segments, DNORM (P=.005) and DAVE (P<.0001) were
both significantly decreased from baseline. In regressing segments,
DNORM did not change, whereas DAVE (P=.0002) significantly
increased from baseline. Change in DAVE differed significantly between
progressing and regressing segments (P<.0001). Differences
in MLD and PS in progressing and regressing segments, having been set
by the classification procedure, were significantly different within
and between progressors and regressors.
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The Figure
demonstrates changes in QCA measures in all,
opposite, adjacent, distal, and proximal stenosis-stable
segments of progressors and regressors. In all
stenosis-stable segments combined (proximal, distal,
adjacent, and opposite), progressors showed a significant increase from
baseline in PS (P=.005), MLD (P=.005), DNORM
(P=.0005), and DAVE (P=.0008), whereas these
measures did not change significantly in stable segments of regressors.
Opposite stable segments of progressors showed significant increases in
MLD (P=.0006), DNORM (P=.001), and DAVE
(P=.001) but no significant change in PS. In contrast, all
measures of opposite stable segments of regressors showed
nonsignificant changes in a reverse direction. Significant differences
between progressors and regressors appeared in MLD (P=.05),
DNORM (P=.02), and DAVE (P=.02) for opposite
stable segments. Finally, distal stable segments of progressors showed
a significant increase in PS (P=.001).
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Compensatory Changes in Relation to Total Occlusions and
Recanalizations
We examined the issue of progression to total
occlusion in
relation to compensatory change in remote stable segments and found
that of 59 progressors with 98 progressing segments, 13 subjects had
segments that progressed to total occlusion. Among the 59 progressors,
24 subjects (41% of progressors) had large MLD increases >0.32 mm in
1 or more stenosis-stable segments. Of these 24
progressors, 6 subjects (25% of progressors with large MLD increases)
had lesions that became totally occluded. The Fisher's exact test for
difference resulted in P=.75.
Among the 19 regressors, 5 subjects had recanalization. Of these 5 patients, 1 subject had no regressing lesions other than the vessel that recanalized. Among the 19 regressors, 6 subjects (32% of regressors) had large MLD decreases >0.32 mm in 1 or more stenosis-stable segments. Of these 6 regressors, 4 subjects (67% of regressors with large MLD decreases) had segments that recanalized. The Fisher's exact test for difference resulted in P=.002.
We compared the mean QCA changes in stenosis-stable segments for subjects stratified by whether or not there was any segment that progressed to a total occlusion. There were no differences in the mean changes between those subjects with segments that progressed to total occlusion as compared with the subjects who did not: PS (1.30 versus 0.87, P=.72), MLD (0.034 versus 0.049 mm, P=.85), DAVE (0.085 versus 0.081 mm, P=.71), and DNORM (0.115 versus 0.106 mm, P=.72). We also compared the mean QCA changes in stenosis-stable segments for subjects stratified by whether or not there was any segment that recanalized. There was a marginal difference for DAVE and DNORM but not for MLD and PS. The mean changes between those subjects with segments that recanalized as compared with those that did not were PS (-0.918 versus -0.041, P=.68), MLD (-0.072 versus 0.028 mm, P=.18), DAVE (-0.118 versus 0.039 mm, P=.06), and DNORM (-0.145 versus 0.031 mm, P=.06).
Compensatory Changes in Relation to
Nitroglycerin Usage
Since all angiographic pairs were matched for
nitroglycerin usage at baseline and follow-up to
exclude the possibility of pharmaceutical vasodilatation, the data
presented in the Figure
represent change between
baseline and follow-up vessel diameters regardless of mechanism,
eg, anatomic and/or functional. Table 3 shows the
magnitude of change in vessel diameters between baseline and
follow-up angiograms by nitroglycerin usage. Two
significant differences (P<.05) were found for progressors
(change in MLD for all stable segments and change in MLD for opposite
stable segments were larger for subjects who did not have
nitroglycerin). No differences were found for
regressors.
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When subjects with nitroglycerin usage were excluded
from the analysis of change in QCA measures in all, opposite,
adjacent, distal, and proximal stenosis-stable segments of
progressors and regressors, patterns similar to those shown in the
Figure were found. In all stenosis-stable segments
combined, progressors showed a significant increase from baseline in
PS, MLD, DNORM, and DAVE (P<.05), whereas these measures
did not change in stable segments of regressors. Opposite stable
segments of progressors showed significant increases in MLD, DNORM, and
DAVE (P<.05) but no significant change in PS. Except for
MLD, all measures of opposite stable segments of regressors showed
nonsignificant changes in a reverse direction.
Correlates of QCA Change
Progressors and regressors were
combined for
multivariate correlation of on-trial clinical,
lipid, lipoprotein, and apo parameters with changes in PS,
MLD, DNORM, and DAVE in opposite stable segments. To adjust for the
magnitude of change in the progressing or regressing segment, changes
in PS and MLD were forced in as model covariates. Table 4
summarizes the variables that are significant
(univariate) correlates of QCA change independent of the
magnitude of change in progressing and regressing segments.
On-trial apo B level, systolic BP, and
diastolic BP were common correlates (negatively) to changes
in MLD, DNORM, and DAVE. On-trial levels of apo B, apo C-III in
whole serum, and apo C-III in heparin precipitate were common
correlates (negatively) to change in MLD and DAVE. In stepwise
regression models (not shown in Table 4), apo B and
diastolic BP were both independently correlated
(negatively) with change in MLD and DAVE, and systolic BP was
multivariately correlated (negatively) with change in
DNORM. When tested univariately (not shown in Table 4),
treatment group was significantly associated with changes in DNORM and
DAVE, with the lovastatin-treated group showing greater
increases in these variables. Treatment group did not enter the
stepwise model for any QCA measure. Thus, the compensatory effects in
stable segments remote from progressing or regressing segments appear
to be potentiated through the reduction of apo B and
triglyceride-rich lipoproteins.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study provides the first serial QCA evidence that coronary artery compensatory dilation occurs during progression of CAD. Furthermore, the data indicate that lesion progression is associated with compensatory increases in segmental diameter of remote parts of the coronary tree. As demonstrated in the Figure
,
progression of lesions in one segment was associated with a significant
increase in average (P=.001), normal (P=.001),
and minimum (P=.0006) lumen diameters in opposite
coronary artery segments. Dilation of segments proximal and
adjacent to, as well as constriction of segments distal to, progressing
lesions is also consistent with vascular compensation in
response to coronary lesion progression. Although the magnitude
of luminal changes in the proximal, distal, and adjacent segments was
comparable to most of those in opposite segments, the limited number of
segments in each of the former categories was too small to demonstrate
statistical significance. Also, luminal changes in the reverse
direction in coronary segments opposite regressing lesions
indicate that vascular compensation may also occur in response to
lesion regression. Our findings of compensatory diameter changes in stenosis-stable segments most likely reflect a chronic change in lumen size consistent with histological1 2 and in vivo3 evidence demonstrating that coronary arteries locally enlarge in response to growing atherosclerotic plaques, thereby preserving lumen area and delaying clinically important lumen stenosis. The significant increase in lumen diameter of opposite segments would tend to normalize total myocardial blood flow while compensating for reduced flow through a vessel where lesion progression has occurred. Recently, compensatory dilation of remote coronary vessels has been demonstrated to occur during acute obstruction of coronary blood flow. During balloon-occluded acute obstruction of blood flow across a single left anterior descending coronary artery lesion undergoing PTCA, acute increase in the magnitude of blood flow and cross-sectional area of the nonoccluded right coronary artery occurred.10 The response and magnitude of blood flow and cross-sectional area in the remote right coronary artery opposite to the acute obstruction in the left anterior descending coronary artery were similar to those changes demonstrated by serial QCA in the present study.
The results from this study have important implications for clinical trials with QCA end points, because statistical analyses of QCA end points on a continuous scale typically average QCA changes over all lesions within a subject. Thus, the effect of progression on diameter means may be mitigated by simultaneous compensatory diameter enlargement in remote coronary segments. In some cases, the magnitude of compensatory change is large. Observed diameter increases in stenosis-stable segments of subjects classified as progressors in this study were as great as 0.84 mm for MLD, 1.32 mm for DNORM, and 0.99 mm for DAVE. The most extreme changes in stenosis-stable segments occurred in segments opposite severe stenoses or opposite to lesions that progressed to occlusion.
Correlates of QCA Change
Experimental evidence strongly
suggests that vasodilation of
coronary arteries is endothelium
dependent11 12 and mediated by release of
EDRF13 14 in response to coronary blood
flow.14 15 16 EDRF-mediated flow appears
to be impaired in
atherosclerotic arteries that fail to dilate in response to an increase
in blood flow.17 18 19 Loss of
EDRF-mediated flow is also
related to elevated serum cholesterol
levels,20 and EDRF-mediated flow is restored without
histological evidence of intimal thinning when serum
cholesterol levels are reduced.21
The remote compensatory coronary artery lumen changes observed in our study most likely reflect flow-mediated vascular changes rather than a focal compensation due to the generalized atherosclerotic process. This is evident since stenosis-stable segments opposite progressing lesions demonstrated an increase in average, normal, and minimal lumen diameters, and this increase was correlated to reduction of apo B levels. After the magnitude of progression or regression was taken into account, apo B was independently correlated to changes in MLD and DAVE of opposite stable segments, with the largest effect on change in MLD. The size and direction of changes in MLD, DNORM, and DAVE are compatible with EDRF-related effects reported by others.17 18 19 The correlation of BP with changes in MLD, DNORM, and DAVE is also consistent with studies in animals that demonstrated that long-term and short-term elevations of BP disturb EDRF-dependent vasodilation.22 23 The univariate correlation of apo C-III (specifically apo C-III in heparin precipitate) with compensatory changes in vessel luminal diameter indicates that triglyceride-rich lipoproteins may play a role in vascular compensatory change.24 25 Finally, our findings are consistent with serial coronary angiographic data reported from the Stanford Coronary Risk Intervention Program (SCRIP) that indicate that vasodilation of segments distal to PTCA sites reflects flow-mediated vascular compensation.26 The extent of this compensation was related to the degree of reduction of LDL cholesterol levels.26 In a similar situation, segments distal to progressing lesions in lovastatin-treated progressors in the present study demonstrated an apparent flow-mediated, significant reduction in lumen diameter, whereas placebo-treated progressors did not (data not shown).
Compensatory Changes in Relation to Total Occlusions and
Recanalizations
Of 24 progressors with the largest increases in MLD
(>0.32 mm)
for stenosis-stable segments, 20 had lesions >90 PS at
baseline or follow-up in progressing segments opposite to the
stenosis-stable segments. Although 6 of these latter
subjects developed total occlusion in the progressing segments opposite
to the stenosis-stable segments at follow-up,
progression to total occlusion was not in itself significantly
associated with these large compensatory changes.
Among 19 subjects classified as regressors, the greatest diameter decreases in stenosis-stable opposite segments were observed in subjects with recanalization (-0.52 mm for MLD, -0.76 mm for DNORM, and -0.68 mm for DAVE). Mean diameters in stenosis-stable opposite segments decreased in all 4 subjects classified as regressors with recanalization that was significantly associated with large compensatory changes (<-0.32 mm, P=.0002). It is possible that mixed lesion change is in itself the result of vascular compensation rather than actual lesion progression and regression occurring simultaneously; 12% of the MARS cohort demonstrated both lesion progression and regression. Caution in interpretation of QCA trials is warranted, and further studies to investigate the impact of vascular compensatory changes in these trials are indicated.
Compensatory Changes in Relation to
Nitroglycerin Usage
Subjects who did not receive nitroglycerin before
angiography consistently demonstrated larger compensatory
vascular changes in response to progressing lesions than subjects who
did (Table 3). Although epicardial3 or
intravascular ultrasound27 is required to verify anatomic
change of the coronary arteries in vivo, these results are
primarily suggestive of functional (vasodilation) change in response to
progressing lesions. Furthermore, these results indicate that
standardized use of nitroglycerin in serial QCA trials
may have a significant mitigating effect on the measurement of
compensatory changes in stenosis-stable segments.
Conclusions
In summary, this study demonstrates that lesion
progression in one
coronary artery segment is associated with significant
increases in arterial diameter in remote coronary
segments. Although not statistically significant, the data also
indicate that lesion regression is associated with a decrease in
arterial diameter in remote coronary segments. In
addition to focal compensatory changes in response to growing
atherosclerotic plaques, our data indicate that remote coronary
artery lumen changes are most likely the result of flow-mediated
vascular compensation. This vascular compensation is enhanced by
lowering apo B and C-III levels and may contribute to the reduction in
clinical coronary events observed in serial angiographic
trials.5 A growing body of data substantiate the results
of this study, which demonstrates by serial QCA for the first time that
coronary artery compensatory dilation occurs in response to
progression of CAD. Finally, our data indicate that compensatory
dilation may be in itself part of the LDL cholesterol– and
triglyceride-rich lipoprotein–lowering treatment
effect, an issue that warrants clarification.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Supported in part by US Public Health Service grants NIH-NHLBI-RO1-HL-49885, RO1-HL-45005, RO3-HL-48399, and RO3-HL-48532 and Merck & Co, Inc.
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Footnotes |
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Reprint requests to Howard N. Hodis, MD, Atherosclerosis Research Unit, Division of Cardiology, University of Southern California School of Medicine, 2250 Alcazar St, CSC-132, Los Angeles, CA 90033.
Received November 29, 1994; revision received March 30, 1995; accepted May 23, 1995.
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