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(Circulation. 1995;91:1403-1409.)
© 1995 American Heart Association, Inc.
Articles |
Elevated Serum Lipoprotein(a) Is a Risk Factor for Clinical Recurrence After Coronary Balloon Angioplasty
From the Cardiovascular Division, University of Virginia School of Medicine, Charlottesville.
Correspondence to Lawrence W. Gimple, MD, Cardiovascular Division, Box 158, Health Sciences Center, University of Virginia, Charlottesville, VA 22908.
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Abstract |
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Background Elevated lipoprotein (Lp) (a) concentrations are associated with coronary artery disease and myocardial infarction. Lp(a) is structurally related to proteins involved in lipid transport, fibrinolysis, coagulation, and cellular mitogenesis and is known to have important physiological interactions with the coagulation and fibrinolytic systems. Because these processes may be important to arterial healing after balloon injury, we hypothesized that elevated Lp(a) concentrations may be associated with recurrence of symptoms and restenosis after balloon angioplasty.
Methods and Results We assessed 240 consecutive patients undergoing coronary balloon angioplasty with measurements of Lp(a), total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein A-I, and apolipoprotein B-100 concentrations from fresh specimens. Patients were evaluated 4 to 6 months after angioplasty for clinical recurrence by repeat angiography if angina had returned or by maximal exercise treadmill testing with thallium imaging if patients remained asymptomatic. Ninety-seven patients (40%) had clinical recurrence; 143 (60%) did not. Patients with recurrence had significantly greater Lp(a) concentrations compared with those without (median, 29 versus 14; P<.0001). Each patient quintile stratified by increasing Lp(a) concentrations had incrementally greater recurrence rates ranging from 27% (lowest quintile) to 60% (highest quintile). By multivariate logistic regression analysis, Lp(a) concentration was the only predictor of recurrence (P<.0001). A subset of frozen, stored serum samples showed a significant decrease in measured Lp(a) concentration over time (mean, 605 days; P<.01).
Conclusions An elevated Lp(a) concentration was a risk factor for clinical recurrence after percutaneous transluminal balloon coronary angioplasty. Other lipid levels or clinical characteristics were not significantly associated with recurrence. When serum was frozen and stored for a prolonged period, Lp(a) concentration decreased over time.
Key Words: lipoproteins • lipids • angioplasty
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Elevated lipoprotein (Lp) (a) concentrations have been shown to be associated with atherosclerotic vascular disease, including an increased prevalence and severity of coronary artery disease,1 2 3 4 carotid artery disease,5 and peripheral vascular disease.6 Acute complications of these chronic conditions—myocardial infarction,7 retinal vascular occlusion,8 and occlusive arterial thrombosis9 —have been strongly correlated with serum Lp(a) concentrations. This increased risk of atherosclerotic vascular disease has been confirmed in diverse patient population groups.10 11
Lp(a) is involved in lipid transport, and its constituent, apolipoprotein (apo) (a), is structurally related to important proteins involved in fibrinolysis, coagulation, and cellular mitogenesis. Lp(a) is known to have physiological interactions with the coagulation and fibrinolytic systems.12 13 14 15 Both Lp(a) and apo(a) stimulate smooth muscle cell proliferation in vitro.16 These observations demonstrate important interactions among Lp(a), lipid metabolism, the coagulation and fibrinolytic systems, and smooth muscle cell proliferation.
Because percutaneous transluminal coronary angioplasty (PTCA) of atherosclerotic coronary obstructions is associated with thrombosis and neointimal hyperplasia, we hypothesized that elevated Lp(a) concentrations may be an important risk factor for clinical recurrence owing to restenosis after angioplasty. However, previous studies examining the relationship between Lp(a) concentrations and clinical recurrence have been contradictory and inconclusive.17 18 Therefore, we examined the relation between Lp(a) concentrations and clinical recurrence in 240 consecutive patients undergoing coronary balloon angioplasty at our institution.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Population
We enrolled 240 consecutive patients undergoing successful PTCA (residual stenosis immediately after PTCA of <50% and no complications through hospital discharge) of one or more native coronary arteries. Exclusion criteria were liver disease (associated with synthetic dysfunction), renal insufficiency (defined as serum creatinine >2.0), steroid-treated immunologic disorders, and uncontrolled diabetes. No patients were using lipid-lowering agents known to affect Lp(a) concentrations (eg, nicotinic acid or N-acetylcysteine).
Laboratory Examinations
Fasting blood samples for lipid
measurements were drawn on the
day of angioplasty from patients without a recent (
1 month)
myocardial infarction and at 1 month after the angioplasty from
patients with recent infarction to allow cholesterol levels and Lp(a)
levels to return to baseline.19 Cholesterol and
triglyceride concentrations were measured enzymatically with a
Boehringer Mannheim Hitachi 736 analyzer. HDL cholesterol
concentrations were measured enzymatically with a Boehringer Mannheim
Hitachi 717 analyzer after precipitation of less dense lipoproteins by
dextran sulfate–magnesium.20 ApoA-I and apoB-100
concentrations were measured by nephelometry on a Beckman Array. Lp(a)
measurements were performed with a monoclonal-polyclonal sandwich
enzyme immunoassay [MACRA Lp(a)] from Terumo Medical Corp. The
coefficient of variation with this method is 2.94%. Serum samples for
Lp(a) were frozen at -70°C, and assays were performed within 4 days
of blood drawing. In a separate set of control experiments (described
below), serum was frozen (-70°C) and stored for 2 years before Lp(a)
measurement.
Definition of Recurrence
Recurrence was defined as either
recurrent ischemic symptoms
requiring repeated angiography associated with 
50% stenosis at the
site of angioplasty (restenosis at any single site was classified as
restenosis in patients with multivessel PTCA) or a positive 6-month
exercise treadmill test with 201Tl scintigraphy showing
redistribution in the vascular territory of an angioplastied artery.
For the few patients (n=7) without repeated angiography or exercise
treadmill testing between 4 and 6 months after PTCA, recurrence was
considered absent in those who remained asymptomatic. Two blinded
reviewers used calipers to measure severity of stenosis before PTCA,
immediately after PTCA, and at follow-up angiography. Exercise
treadmill testing was performed with a standard Bruce protocol, and
quantitative planar thallium images were acquired and interpreted as
previously described by our nuclear cardiology
laboratory.21 22 Observers blinded to all data other
than
symptom status, angiographic data, and exercise results assigned
recurrence status. Individual physicians without knowledge of Lp(a)
concentrations made the decision to perform repeated angiography or
revascularization.
Assessment of Freezing and Storage on Lp(a) Measurement
Results
The effect of freezing (-70°C) and long-term storage
of serum
samples on measured Lp(a) concentration was assessed on serum obtained
from 10 patients. Lp(a) concentrations were measured within 4 days of
serum being obtained and again after serum was frozen and stored for
more than 1 year. To determine the effect of a single freeze-thaw cycle
after short-term storage, fresh serum samples were assayed for Lp(a)
concentrations, frozen (-70°C), and reassayed after 4 days.
Statistical Methods
Data are expressed as mean±SD or
as median with ranges.
Patients with and without recurrence were compared with unpaired
Student's t tests (for continuous variables) or with
Fisher's exact tests (categorical data).23 For variables
with nonnormal distributions, eg, Lp(a), nonparametric analysis
(Mann-Whitney) was used. Logistic regression analysis was performed
to determine predictors of recurrence with the variables listed in
Tables 1
and 2.24 Stepwise logistic
regression techniques
were used to determine multivariate predictors of recurrence. Based on
the final logistic model, the probability of recurrence for each Lp(a)
concentration was plotted. Odds of recurrence and recurrence rates were
calculated for each quintile of Lp(a) concentration. Student's
t test (paired) was used to compare Lp(a) concentrations
in fresh and stored samples. Differences were considered significant
when the probability value was <.05 (two-sided). When multiple
comparisons were performed, the Bonferroni correction was applied.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Classification of Recurrence
Of the 240 patients studied, clinical follow-up was achieved in 100% of patients, and angiographic or thallium imaging studies were performed between 4 and 6 months in 233 of the 240 (97%). On the basis of prospectively defined criteria for recurrence, 97 patients (40%) were classified with recurrence and 143 (60%) without recurrence. Of the 240, 85 patients (35%) underwent repeated target vessel revascularization within 6 months owing to recurrent symptoms and critical arterial renarrowing.
Recurrence was established as follows: 108 of 240 patients (45%) underwent repeated coronary angiography within 6 months for suspected restenosis; 90 (83%) had angiographic restenosis at one or more angioplasty sites, 10 (9%) did not have angiographic restenosis, and 8 (7%) underwent repeated angiography less than 4 months after PTCA without restenosis (all had negative exercise thallium scans at 6 months and were classified without recurrence). Of the 132 patients who did not undergo repeated angiography, 125 (95%) had exercise treadmill testing with quantitative 201Tl imaging; 118 (94%) of these had negative 201Tl images and were classified as not having recurrence, whereas 7 (6%) had 201Tl redistribution in the vascular territory of the angioplasty artery and were considered to have recurrence. Finally, 7 of the 240 patients (3%) had neither repeated angiography nor exercise testing; all were asymptomatic and were classified as not having recurrence.
Associations With Recurrence
Table 1
shows the
clinical and angiographic
characteristics of the 240 patients and the relation of clinical and
laboratory factors to recurrence. None of these clinical descriptors
was associated with recurrence.
Table 2 compares total
cholesterol, triglyceride, HDL,
LDL, apoA-I, and apoB-100 concentrations; LDL-HDL ratio; and Lp(a)
concentrations in patients with and without recurrence. By logistic
regression analysis, only Lp(a) concentrations were associated with
recurrence (P<.0001). No other lipid measurements were
associated with recurrence, with only a trend toward higher LDL
concentrations in patients with recurrence (P=.07). By
stepwise logistic multivariate analysis of laboratory and clinical
parameters, Lp(a) concentration was highly associated with risk of
recurrence (P<.0001), and after Lp(a) concentrations were
accounted for, no other variable was significantly associated with
recurrence. Recurrence rates and Lp(a) concentrations were not
different in the 58 patients (24%) receiving than those not receiving
lipid-lowering therapy. The same relations of Lp(a) to restenosis were
found when only Caucasian patients were analyzed.
Fig 1
demonstrates the cumulative distribution of Lp(a)
concentrations in the entire patient cohort and in the subgroups with
and without recurrence. The value on the ordinate represents
the cumulative percent of patients with Lp(a) concentrations less than
or equal to the corresponding value on the abscissa. The cumulative
percentage of each patient group having an Lp(a) concentration less
than any given value can be determined with this graph. For example,
the horizontal dashed line at 50% corresponds to the median Lp(a)
concentration for each patient group. It can be seen that the group
with no recurrence had a median Lp(a) concentration of 14 (first
vertical dashed line), which is significantly less than the median
value of 29 in the recurrence group (second vertical dashed line). It
can be also be seen that 98% of patients in the entire cohort had
Lp(a) levels 80.
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Fig 2 (top) illustrates the
recurrence rates based
on Lp(a) concentration by quintile, demonstrating increasing recurrence
rates with increasing Lp(a) concentration. For the lowest quintile of
patients, the recurrence rate was 27%, increasing to 60% for patients
in the highest quintile (P<.0001). Fig 2 (bottom)
shows
that the odds ratio (OR) for recurrence in patients in the highest
Lp(a) quintile relative to patients in the lowest Lp(a) quintile is
4.1:1.
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Fig 3 uses logistic regression to model the
recurrence
rate for each Lp(a) value. The plotted data represent observed
recurrence rates for the median value for each patient quintile. The
curve is a plot of the logistic model with the following equation:
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where P(r) is the probability of recurrence or the recurrence rate. With this plot, the recurrence rate for any given Lp(a) value can be estimated in this and similar populations.
Associations With Need for Repeated Target Vessel
Revascularization
Repeated coronary angiography and target vessel
revascularization were performed only for recurrent angina and critical
arterial renarrowing. No clinical descriptors were significantly
associated with repeat target vessel revascularization. Among lipid
values, only the Lp(a) concentration was associated with repeat
revascularization by logistic regression analysis
(P<.001). The median Lp(a) concentration in the 85 patients
requiring repeated revascularization was significantly greater than in
the 155 patients not requiring revascularization (28.0 versus 16.0,
P<.001). By stepwise logistic regression analysis,
Lp(a) concentration was the only significant multivariate correlate
with repeated revascularization (P<.001).
Assessment of Freezing and Storage on Lp(a) Measurement
Results
Lp(a) concentrations were measured from fresh serum samples
(n=10)
and from simultaneously drawn samples that were frozen and stored for
605±110 (range, 393 to 697) days. The mean Lp(a) concentration from
fresh samples was significantly greater than in stored samples
(29.5±24.5 [range, 1 to 72] mg/dL versus 6.8±6.8
[range, 0 to 21]
mg/dL, P<.01). Thus, freezing and long-term storage
resulted in substantial loss of measured Lp(a) (Fig 4).
In contrast, fresh samples (n=13) that were assayed, frozen for 4 days
(-70°C), and reassayed did not show significant degradation
(32±23
versus 30±23; P=NS, r=.97).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Role of Lp(a) and Other Lipids in Restenosis and Clinical Recurrence
Our data demonstrate that an elevated Lp(a) concentration is a significant risk factor for clinical recurrence defined as ischemic symptoms with critical arterial renarrowing within 6 months after coronary angioplasty. Additionally, elevated Lp(a) concentration is strongly associated with the need for repeated target vessel revascularization for recurrent angina and critical arterial renarrowing. Consistent with previous observations,25 Lp(a) concentrations were not normally distributed in our population but were skewed toward lower values. When patients were stratified into quintiles based on serum Lp(a) concentration, each progressively higher quintile was associated with incrementally greater recurrence rates. For example, the lowest quintile had a recurrence rate of 27% compared with 60% in the highest quintile. No other lipid concentration, lipid ratio, or patient-related factor was significantly correlated with recurrence. This finding may have important implications in selecting appropriate patients for balloon angioplasty, furthering our understanding of the mechanism(s) of clinical recurrence caused by restenosis, and potentially in limiting restenosis if effective measures to lower Lp(a) concentrations result in lower restenosis rates.
The data reported in the present study and published previously by others26 27 demonstrate that measured Lp(a) concentrations decrease with time when specimens are frozen and stored. This may partially explain the contradictions in previous reports on the relation between Lp(a) and restenosis. Shah and Amin18 did not find a significant difference in Lp(a) concentrations between patients with and without restenosis. In their study, blood samples were frozen and stored for at least several months before measurement of Lp(a) concentrations. The negative results may have been influenced by an artifactual decrease in measured Lp(a) concentrations after storage and by a small sample size (n=68). The mean Lp(a) concentration observed in that study was only 7±7 mg/dL, a value much lower than the mean concentrations reported from the Framingham Study in a cohort of patients who were free of cardiovascular disease and not on lipid-lowering medications25 and much lower than values reported by Dahlen et al1 (mean, 19.6 mg/dL; median, 10.3 mg/dL) in a mixed population referred for coronary angiography with a suspected diagnosis of coronary artery disease. A more recent study also concluded that there was no relation between Lp(a) concentration and restenosis.28 Only 62 patients were included in this study, and Lp(a) concentrations in the group with restenosis were nearly twice as great as in the group with no restenosis, suggesting a type II error. In addition, serum samples were frozen and stored for a mean of 44 days. Hearn et al17 did not examine a consecutive angioplasty cohort but only patients returning for angiography within 10 months of PTCA with suspected restenosis. In this small population (n=69) with a high incidence (71%) of restenosis, Lp(a) was significantly associated with restenosis, and the highest quintile of patients had an OR of 11:1 compared with the lowest quintile. This OR is greater than that reported in our study (4.1:1), possibly reflecting a selected patient cohort that was not typical of a consecutive angioplasty population.
We found no statistically significant relation between total cholesterol, triglyceride, HDL, LDL, apoA-1, or apoB-100 concentrations or LDL-HDL ratio and the risk of recurrence. Some previous investigators reported that low HDL concentrations18 or elevated total cholesterol–HDL ratios and triglyceride concentrations29 are associated with restenosis, while others have not.17 Thus, there are currently no consistent data to support the hypothesis that lipid concentrations other than Lp(a) are important risk factors for restenosis.
Assessment of Recurrence Risk Before Angioplasty
Patients
needing revascularization for coronary artery disease can
be treated with either surgical or percutaneous techniques. Current
nonsurgical techniques have advanced and have high initial success
rates, but all available percutaneous techniques are plagued by
restenosis and a need for repeated intervention. In determinations of
whether surgical or percutaneous techniques would be the most suitable
strategy, it would be helpful to be able to assess the risk of
recurrence for an individual patient. Many studies have looked at
patient-related and lesion-related variables to assess this risk of
restenosis.30 31 32 33 34 35 36 37 38 39
Results of studies examining
patient-related factors (including diabetes mellitus, unstable angina,
and duration of angina) have been contradictory with no consistent
correlations with
restenosis.30 31 32 33 34 35 36 37 38 39
In contrast,
lesion-related factors (including severity of stenosis before
angioplasty, stenosis length, and the presence of collaterals) have
been correlated more consistently with restenosis.30 The
present study suggests that the measurement of Lp(a) concentration
will allow a more accurate assessment of an individual's risk of
recurrence and may help in the selection of the most appropriate
revascularization strategy for an individual patient.
Possible Pathophysiological Mechanisms
The mechanism(s)
responsible for restenosis are poorly understood.
Intimal hyperplasia and arterial mural thrombosis are thought to
contribute to the processes accounting for late luminal renarrowing
after angioplasty. Lp(a) is known to be a risk factor for
atherosclerotic obstruction in other arterial
beds1 2 3 4 5 6
and
has been associated with acute thrombotic complications of
atherosclerosis, including acute myocardial infarction,7
myocardial infarction in patients without angiographically apparent
atherosclerosis,40 lack of recanalization with
thrombolytic therapy for myocardial infarction,15 retinal
vascular occlusion,8 and occlusive peripheral arterial
thrombosis.9 The structural and physiological properties
of Lp(a) make it a possible candidate molecule for participation in the
process of restenosis. The apo(a)-LDL complex is an important component
of the lipid transport system. Apo(a) is structurally related to
important proteins involved in fibrinolysis (plasminogen, tissue
plasminogen activator, urokinase), coagulation (prothrombin; factors
VII, IX, X, and XII; and protein C), and cellular mitogenesis
(hepatocyte growth factor). Physiologically, Lp(a) is known to have
important interactions with the coagulation and fibrinolytic systems,
including fibrin binding12 and subsequent immobilization
of LDL within atherosclerotic plaques,41 inhibition of
plasminogen and tissue-type plasminogen activator binding to
fibrin,13 14 attenuation of TPA activity, and
impaired
clot lysis.12 These interactions, which occur at sites of
deep arterial injury associated with balloon angioplasty, may be
important in restenosis. It has been suggested that the thrombotic
"scaffold" resulting from balloon angioplasty may form the matrix
on which intimal hyperplasia occurs.42 Furthermore,
several coagulation proteins, including those structurally related to
apo(a) (thrombin, Xa), have been demonstrated to be mitogenic for
smooth muscle cells in vitro.43 44 Grainger et
al16 demonstrated that both Lp(a) and apo(a) can stimulate
smooth muscle cell proliferation in vitro by inhibiting plasminogen
activation and consequently the activation by plasmin of latent
transforming growth factor-ß. Thus, the identification of Lp(a) as an
important risk factor for restenosis may lead to further insights into
the mechanisms responsible for restenosis. Studies regarding the
usefulness of pharmacological agents to lower Lp(a) concentrations
(nicotinic acid, N-acetylcysteine) and their effects on
restenosis may be warranted.
Study Limitations
There is controversy regarding the most
appropriate methodologies
to define recurrence and restenosis after coronary
interventions.45 46 47 Consistent with
recent recommendations
for clinical trials,48 we prospectively chose a clinically
relevant definition of recurrence that required recurrent symptoms with
angiographically demonstrated restenosis or inducible ischemia in the
myocardial distribution of the previously dilated coronary artery.
Maximal exercise treadmill testing with quantitative 201Tl
scintigraphy, which in our laboratory has a very high sensitivity and
specificity for identifying significant coronary
stenoses,21 was used to assess clinical recurrence in
asymptomatic patients. A negative maximal exercise test with
quantitative thallium scintigraphy probably identified the asymptomatic
patients with very little, if any, angiographic restenosis. We also
assessed an alternative definition of recurrence suggested by Kuntz and
Baim.48 Patients who underwent repeated revascularization
of the target vessel because of recurrent angina and critical arterial
renarrowing of the target vessel within 6 months were classified as
having recurrence. With this definition in our patient cohort, Lp(a)
levels also correlated highly with clinical recurrence. This definition
seems appropriate because borderline luminal diameter narrowing by
quantitative coronary angiography (40% to 70%) correlates poorly with
both clinical symptoms and prognosis.49
Lp(a) concentrations in serum are known to be under genetic control and relatively constant throughout life.50 51 Lp(a) concentrations, however, do fall during the month after myocardial infarction and return to baseline at 1 month.19 We therefore measured Lp(a) concentrations in patients with recent infarction after 1 month. It has been noted that the frequency distribution of Lp(a) concentrations varies across different populations.52 53 54 In our patient population, patients were either Caucasian (90%) or African American (10%), and no significant differences were seen between these two patient subgroups.
Received August 4, 1994; revision received September 29, 1994; accepted October 9, 1994.
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