(Stroke. 1995;26:1841-1848.)
© 1995 American Heart Association, Inc.
Articles |
Lipoprotein(a) Serum Concentration and Apolipoprotein(a) Phenotype Correlate With Severity and Presence of Ischemic Cerebrovascular Disease
From the Institute for Medical Biochemistry, Karl-Franzens Universität Graz (G.J., W.P., Q.C., J.G.) and Hospital Barmherzige Brüder Eggenberg (P.K.), Graz, Austria; Organon Teknika/Biotechnology Research Institute, Rockville, Md (W.C.T.-P., P.F.M., B.T.B., J.H.R.); and Organon Teknika Corporation, Durham, NC (A.G.S.).
Correspondence to Dr G. Jürgens, Institute for Medical Biochemistry, Karl-Franzens Universität Graz, Harrachg 21, A-8010 Graz, Austria. E-mail juergens@bkfug.kfunigraz.ac.at.
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Abstract |
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Background and Purpose Serum lipoprotein(a) [Lp(a)] levels are genetically determined and considered to be an independent risk factor for atherosclerosis. The aim of this study was to provide a complete analysis of Lp(a) serum levels, apolipoprotein(a) phenotypes, and other lipid parameters for different forms of severity of symptomatic ischemic cerebrovascular disorders as well as for different stages of carotid atherosclerosis.
Methods Lp(a) concentration, apolipoprotein(a) phenotype, triglyceride, low-density lipoprotein, high-density lipoprotein, and total cholesterol levels of blind-coded specimens as well as degree of carotid artery stenosis were assessed in a consecutive series of patients with ischemic cerebrovascular disease. We evaluated 265 male (34%) and female (66%) patients (mean age, 51±7.4 years) with transient ischemic attack (55.8%), prolonged reversible ischemic neurological deficits (28.3%), and cerebral infarction (15.9%) as well as 288 male (30%) and female (70%) control subjects (mean age, 51±7.1 years). All subjects were white.
Results Lp(a), total, and low-density lipoprotein
cholesterol were statistically significantly elevated in
all patients compared with control subjects. Lp(a) correlated with the
severity of symptomatic cerebrovascular disease and the
degree of carotid stenosis. Logistic regression
analysis revealed Lp(a) as the best single marker for the
presence of cerebrovascular disease (P<.001) followed by
high-density lipoprotein cholesterol
(P=.003) and triglycerides (P=.049).
With a cutoff of 20 mg/dL of Lp(a), the odds ratio for a subject to
have had ischemic stroke with elevated Lp(a) was 20.3 and 23.7
depending on the method of the Lp(a) estimation, whereas the odds ratio
when the sonography score was >0 was 15.4. The investigation of the
distribution of the apo(a) phenotypes revealed that 16.73% of
the control subjects had major isoforms 
580 kD molecular weight (B,
F, S1, S2) versus 42.65% of the patients' group (P<.001).
These isoforms were also present in 14.71% of all individuals with
a sonography score of 0 but in 52.30% of all individuals with a
sonography score >0 (P<.001).
Conclusions This case-control study shows that an elevated Lp(a) level is the primary factor associated with the presence of ischemic cerebrovascular disease and that the increased portion of the smaller-molecular-weight apo(a) isoforms in patients and individuals with a sonography score >0 points toward an inherited predisposition for this disease.
Key Words: apolipoproteins • cerebrovascular disorders • lipoproteins • risk factors
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Elevated serum concentrations of Lp(a) have been strongly correlated with increased risk of premature cardiovascular disease.1 In an early study enhanced serum Lp(a) levels were also found to be associated with cervical atherosclerosis.2 3 Such findings were verified recently in ischemic stroke patients,4 hypercholesterolemic men with early atherosclerotic plaques,5 and heterozygous FH patients and subjects with asymptomatic carotid atherosclerosis.6 7 Furthermore, Lp(a) was also reported to be of special importance and an independent risk factor for various forms of ischemic stroke in white,3 8 9 Japanese,10 11 12 and Chinese13 populations.
Lp(a) serum levels and apo(a) size heterogeneity are under genetic control. Six isoform categories of apo(a), differing in molecular mass, designated F, B, S1, S2, S3, and S4 (which are increasing in size) and an inverse relationship between apo(a) size and Lp(a) serum concentrations were described for a white population.14 More recently, Marcovina et al15 described a seventh isoform category, S5. The molecular weight of apo(a) varies widely among individuals, with reports of as many as 34 different alleles.16 The low apo(a) phenotypes were found more frequently among white FH patients with coronary heart disease and in Chinese with cardiocerebrovascular diseases.17 18
Although several reports exist showing correlations between Lp(a) serum levels and carotid artery disease or different forms of ischemic stroke as well as the distribution of apo(a) phenotypes in cerebrovascular patients, no study provided a complete analysis of Lp(a) serum levels, apo(a) phenotypes, and different stages of symptomatic ischemic cerebrovascular disorders as well as a sonographic investigation of the carotid arteries. Furthermore, we used three different analytical procedures to ascertain any influence of the estimation technique for monitoring Lp(a) serum levels.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients and Control Subjects
Two hundred sixty-five patients (34% male and 66% female) suffering from symptomatic ICD were recruited consecutively from the Department of Neurology of the Hospital Barmherzige Brüder Eggenberg in Graz, Austria, within a period of 4 months. Two hundred eighty-eight control subjects (30% male and 70% female) were from a consecutive series of healthy subjects consulting the hospital for a medical control examination to participate in a screening program within the same period. All subjects were white. The study was approved by the ethics committee of the hospital. Fifty-six percent of the patients had diagnosed TIA, 28.5% had PRIND, and 15.5% had CI or MCI. Patients excluded from the study included those with an ischemic stroke that occurred <2 months previously and history of coronary artery disease. Control subjects had an absence of history of coronary artery disease as well as an absence of history of or any signs of ICD. Peripheral arterial occlusive disease was excluded by means of an ultrasound investigation. All individuals included in the study tested negative for thyroid dysfunction; did not suffer from inflammatory, liver, endocrine, neoplastic, or renal disease; and were not on therapies known to influence Lp(a) levels such as inhibitors of hydroxymethylglutaryl-CoA reductase,19 20 stanozolol, or niacin.21 22 However, hormonal treatment of menopause was not recorded. Thus, the influence of hormonal drugs on Lp(a) levels of the female population cannot be excluded. However, no significant differences were found when we calculated the mean and median of the age of the female control subjects versus patients using the Mann-Whitney two-sample test. Subjects suffering from diabetes mellitus had levels of fasting blood glucose >130 mg/dL. Smoking habits were not recorded in this study, since it has been our experience that the answers given by the subjects are highly unreliable. Because hypertensive drugs are not known to influence Lp(a) levels, subjects with normal blood pressure who were taking hypertensive drugs were not separated from those who were not. The demographics of the patient and control populations stratified by clinical symptoms are shown in Table 1
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All individuals in this study were subjected to sonographic
investigations of the extracranial carotid arteries at the time of
entry into the study. A duplex sector scanner with a frequency of 7.5
MHz and a triplex linear scanner with a frequency of 5.0 MHz
(Ultramark9, ATL) were used for imaging. With this combination of
real-time B scan imaging it became possible to achieve a degree of
resolution sufficient for the detection of even small ulcerated lesions
of the arterial wall of the extracranial arteries. The
operator was without knowledge of the patient's lipid
parameters. The degree of stenosis of these
arteries was scored according to the following criteria: 0, no
atherosclerotic lesions; 1, discrete atherosclerotic lesions on one
side (<20% stenosis); 2, 20% to 50% stenosis on one
side or discrete atherosclerotic lesions on both sides; 3, 50% to 70%
stenosis on one side or 20% to 50% stenosis on both
sides; and 4, stenosis >70% on one side or 50% to 70% on
both sides or occlusion of one carotid artery on one side. The
sonography score of the control subjects and the patients stratified by
clinical symptoms is also shown in Table 1
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Lipoprotein Assays
Lp(a) levels of blind-coded serum specimens were determined
by the Apo-Tek Lp(a) ELISA Test System (Perimmune, Inc). A Reader 530
(Organon Teknika nv) was used to monitor absorbance and calculate the
results by means of linear regression. Previously this assay was shown
to quantitate the Lp(a) concentration on an equal molar basis, ie, the
apo(a) isoform had no influence on the measurement of the Lp(a)
concentration.23 Lp(a) serum samples were also estimated
by means of a time-resolved FIA24 with the use of
commercially available polyclonal anti-Lp(a) and anti-apoB antisera
(rabbit) (Behring AG). Since early studies indicating Lp(a) as a risk
for ICD were performed by means of the rocket IE
method,2 3 8 Lp(a) levels were also measured in 123
randomly selected serum samples by the rocket IE method,24
applying the anti-Lp(a) antiserum from Behring. Calibration of all
assays was performed with the use of calibrators and controls from the
Apo-Tek Lp(a) ELISA Test System. The calibrator,
high-concentration, and low-concentration controls from this
kit were neat serum specimens that were quantified in terms of Lp(a)
particle mass by the Northwest Lipid Research Laboratories (Seattle,
Wash) with a sandwich ELISA with the use of an anti-apo(a) capture
antibody and an anti-apoB detection antibody. Serum specimens were
withdrawn after 12 to 14 hours of fasting and stored at -20°C after
collection for no more than 1 month and thawed immediately before Lp(a)
testing. All Lp(a) estimations were made in duplicate. There was a very
good correlation between the three methods of Lp(a) estimation, with
correlation coefficients of .969 between the ELISA and the rocket IE
methods, .956 between the ELISA and the FIA methods, and .973 between
the FIA and the rocket IE methods. Western blot analysis was
performed with the anti-Lp(a) antiserum from Behring, and the apo(a)
isoforms were designated according to the nomenclature reported
previously.14 15 The apo(a) isoform standard used was from
Immuno AG. The detection limit of the assay was 2 mg/dL.
Serum lipids and lipoprotein levels other than Lp(a) were measured by single estimation within 2 days after blood withdrawal, and the blind-coded serum specimens were stored at 4°C. Total cholesterol was determined enzymatically with the use of reagents and reference standards from Biotrol. For HDL cholesterol estimation, the precipitation reagent from Merck was used. LDL cholesterol was calculated from the peak area and intensity obtained by scanning the ß-band on cellulose-acetate electrophoresis by an improved method based on the techniques described earlier.25 26
Statistical Analysis
For comparisons of the parameters between the
control and the patients' groups shown in Table 1, the
nonparametric Mann-Whitney two-sample test for unpaired
data or Fisher's exact test was applied to determine whether
differences exist within the population demographics with respect to
sex, age, height, weight, blood pressure, and incidence of diabetes.
Analyses were performed with the use of NUMBER CRUNCHER
STATISTICAL SYSTEM software version 5.03 (NCSS) according to
Campbell and Machin.27 Sonography score differences within
each patient population compared with the control population were
assessed statistically by ridit analysis.28 ANOVA
of log-transformed data,29 followed by Dunnett's
procedure,30 was used to construct 95%
simultaneous confidence intervals of the differences
between the means of the lipid parameters of the control
and the multiple patients' groups in Table 2. Since Lp(a) and
triglyceride serum levels are log-normal populations,
not following a gaussian curve, logarithms were used in the
analysis. Partial correlation coefficients were calculated by
MANOVA with ICD category as a classification variable.
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Logistic regression analysis31 was applied to
assess the relative importance of possible explanatory variables
for ICD (Table 3). Because of the nonnormal distributions of
lipid/lipoprotein measurements, base 10 logarithms were taken before
the analysis. A constant of 0.1 was added to Lp(a) values
before transformation to avoid problems with taking the log of zero.
Except for the Mann-Whitney and Fisher's exact tests, all calculations
were performed with SAS/STAT software.29
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To determine the optimum Lp(a) concentration cutoff value to
differentiate individuals who have had symptomatic ICD
(patients) from those who have not had ICD (control subjects), an ROC
curve was generated by plotting the ratio of the true-positive to
the false-negative rate for each 2x2 contingency table of disease
and Lp(a) condition dichotomies generated by varying the cutoff values
versus Lp(a) concentration. The optimal setting was chosen to maximize
the area under the curve formed by the focus of the points generated
for all cutoffs. The optimum Lp(a) concentration cutoff for identifying
individuals at risk was 20 mg/dL. The odds ratios (Table 4) were
calculated according to Campbell and Machin.32
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Comparisons of apo(a) polymorph and phenotype frequencies
between groups (eg, patients versus control subjects, sonography
score=0 versus sonography score >0, Table 7) were carried out with the
use of Fisher's exact test.27 These calculations were
performed with the use of NUMBER CRUNCHER STATISTICAL
SYSTEM software version 5.03.
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Results |
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The group of patients with clinically evident ICD who had suffered from various forms of ischemic stroke did not statistically significantly differ from the group of control subjects regarding sex, age, height, weight, blood pressure, and incidence of diabetes but differed highly significantly regarding the sonography score (Table 1
). In regard to the lipid parameters, HDL
cholesterol was significantly lower only in the group of
patients with PRIND. However, all groups of patients showed
statistically significant higher total and LDL cholesterol
levels and Lp(a) concentrations than the control subjects (Table 2). There was a weak correlation of Lp(a) with total
(r=.11, P<.02) and LDL (r=.11,
P<.02) cholesterol but not with HDL
cholesterol (r=.08, P<.09) or
triglycerides (r=.06, P<.23).
A comparison of the lipid and lipoprotein serum values between those
with a carotid artery sonography score of 0 and those with scores >0
is shown in Table 2. Total cholesterol,
triglycerides, and LDL cholesterol as well as
Lp(a) showed increasing serum concentrations with progression of the
narrowing of the carotid arteries, yet only the Lp(a) serum values of
subjects with sonography scores of 1, 2, 3/4 and the LDL
cholesterol levels of subjects with sonography scores of 2
and 3/4 were statistically significantly different from individuals
with sonography score of 0.
To estimate the primary factor(s) associated with the presence of ICD,
logistic regression analysis was applied. Five increasingly
severe levels of ICD were considered (ie, no evidence of ICD, TIA,
PRIND, CI, and MCI). The list of potential explanatory variables
included sex, age, height, weight, systolic and diastolic
blood pressure, and total cholesterol,
triglyceride, HDL cholesterol, LDL
cholesterol, and Lp(a) levels. The analysis
indicated that Lp(a) was most strongly associated with the presence of
ICD (P<.001), followed by HDL cholesterol
(P=.003) and triglycerides (P=.049)
(Table 3).
Because this was a retrospective observational unmatched
case-control study, odds ratios were calculated to give a
reasonable estimate of the relative risk of a disease. By generating an
ROC curve, we determined the optimum Lp(a) concentration cutoff for
identifying patients with ICD from control subjects to be 20 mg/dL.
With this cutoff, the odds ratio estimating the relative risk of
ischemic stroke with elevated versus nonelevated Lp(a) levels
was 20.3 based on the ELISA results and 23.7 based on the FIA results.
In comparison, the odds ratio when the sonography score was >0 was
15.4 (Table 4). Lp(a) measurement in conjunction with
LDL cholesterol >130 mg/dL did not substantially change
the odds ratios. However, for subjects with LDL cholesterol
130 mg/dL, the odds ratios were lower, ie, 6.59 (ELISA) or 9.47
(FIA).
In addition, with this cutoff the odds ratios for a person to have had ICD increased significantly stepwise with the severity of ischemic stroke, ie, from TIA to PRIND to CI and MCI. This stepwise increase in the odds ratio was also seen when LDL cholesterol was >130 mg/dL.
The cutoff of 20 mg/dL Lp(a) was also used to examine the distribution
of the population stratified by sonography score, as shown in Table 5. The data are based on the ELISA estimation. In the
group with a sonography score of 0, only 8 individuals had Lp(a) levels
20 mg/dL, while 333 individuals had levels below the cutoff. In the
group with a sonography score of 1, 98 individuals (ie, 77% of the
total) had Lp(a) levels below the cutoff. Of these individuals, 67%
had LDL cholesterol >130 mg/dL or total
cholesterol >240 mg/dL and would have been considered at
risk because of elevated LDL and/or total cholesterol. In
the group with a sonography score of 2, 25 individuals (or 42% of the
total) had Lp(a) levels below the cutoff. Of these individuals, 81%
had elevated LDL or total cholesterol levels. Finally, two
individuals in the group with a sonography score of 3 had Lp(a) levels
below the cutoff, but both individuals had elevated LDL and total
cholesterol levels. Odds ratios for estimating the relative
risk of carotid artery stenosis with elevated (versus
nonelevated) Lp(a) levels were also found to increase strongly from a
low to a high value in relation to the degree of stenosis (data
not shown). The close relationship between Lp(a) serum levels and the
severity of carotid atherosclerosis expressed by the
sonography score is graphically demonstrated in the
Figure.
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An inverse relationship exists between Lp(a) serum concentration and
the molecular weight of apo(a).15 We also found an inverse
relationship between Lp(a) serum concentration and apo(a) molecular
weight in the group of patients and of subjects with a sonography score
>0 (Table 6). There were no differences between the
ELISA and FIA data versus the phenotype. Regarding the role of
apo(a) phenotypes for ICD, we found that 70.2% (n=113) of all
individuals with the major isoforms 580 kD molecular weight (B, F,
S1, S2; n=161) had suffered from symptomatic ICD. As for
the sonography score, 68.9% of the subjects with these isoforms had a
sonography score >0 (n=111; 100 patients, 11 control subjects). We
also found that the frequencies of these isoforms differed highly
significantly (P<.001) between the control subjects
(16.73%) and the patients (42.65%) or between individuals with
sonography score of 0 (14.71%) and >0 (52.30%) when compared with
Fisher's exact test (Table 7).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study showed that elevated Lp(a) serum levels are found in ischemic stroke patients and correlate well with carotid artery atherosclerosis, which supports early investigations on that topic.2 3 8 Statistically, as one might expect, total cholesterol, LDL cholesterol, and Lp(a) serum levels differed highly significantly between patients and control subjects. Logistic regression analysis weighted elevated levels of Lp(a) most heavily as a marker of ICD risk, followed by low HDL cholesterol and elevated triglycerides. Compared with coronary heart disease, our data fit well with the results obtained by Dahlen et al33 on angiographically documented coronary artery disease.
Since the number of patients investigated was much higher in the present study than in previous studies,2 3 8 9 11 12 it was possible to investigate if and how Lp(a) correlated with the different forms of ischemic stroke, ie, with the severity of the disease. Odds ratios comparing ischemic stroke frequencies in the presence and absence of elevated Lp(a) levels (>20 mg/dL) were unexpectedly high in the case of CI or MCI. The probability of suffering from milder forms of ischemic stroke such as TIA or PRIND was lower but was still much higher than expected when total or LDL cholesterol was elevated. The highest odds ratios were obtained when Lp(a) levels >20 mg/dL based on the ELISA estimation were combined with total cholesterol levels >240 mg/dL. Based on the FIA estimation, Lp(a) >20 mg/dL alone or with LDL cholesterol >130 mg/dL yielded the highest odds ratios. Thus, Lp(a) was determined to be a very valuable tool for identifying individuals suffering from ICD.
The high discriminating power of Lp(a) serum levels obtained in this study is probably due to the strict criteria applied to include individuals. Because atherosclerosis is a "silent" disease, very often control subjects are merely asymptomatic atherosclerotic individuals. We believe that this confounds studies in which one is examining the association of atherosclerotic disorders and possible risk factors such as Lp(a). Therefore, we took extra precautions in selecting our control population. Apart from the criteria valid for all individuals, control subjects had an absence of history or any signs of symptomatic ICD. Peripheral arterial occlusive disease was excluded by means of ultrasound investigation. Moreover, the control population included only subjects that had tested negative for thyroid dysfunction, an important point when one considers that Lp(a) serum levels were described to be elevated in hypothyroidism.34 Additionally, 88% of the control subjects had a sonography score of 0, ie, there was no evidence of atherosclerosis. Thus, the arithmetic mean of the Lp(a) serum values of the control subjects of 6.83±8.19 mg/dL obtained by the FIA in this study is very low but in good agreement with the arithmetic mean of 4.0±5.3 mg/dL in subjects with no plaques in the carotid arteries.2 In that first investigation on the correlation of Lp(a) with plaque formation in the carotid arteries, Lp(a) was measured with the rocket IE method.2 The arithmetic mean of the Lp(a) serum values of the control subjects obtained by ELISA was somewhat lower (2.26±7.70 mg/dL) than that obtained by FIA in the present study and by the rocket IE method in the former study.2 This is probably due to the fact that a linear regression curve fit was used rather than a point-to-point curve fit because of the size of the study.
This study as well as the other investigations on Lp(a) in ischemic stroke patients referred to in this article were retrospective studies. Since Lp(a) was found to function as an acute-phase reactant,35 36 one could argue the possibility that Lp(a) levels are elevated as a result of the event of a stroke. Lp(a) serum concentrations showed a transient elevation, reaching the maximum at 8.5±3.0 days after an acute myocardial infarction, as studied in 21 patients.36 In another study, which followed Lp(a) serum levels after myocardial infarction in 13 patients, a transient increase was found at day 14, but at day 42 the Lp(a) levels had returned to values obtained at day 1 after the acute event, as did all lipid and lipoprotein values except for apoA-I, which remained depressed.37 However, the criterion for the patients included in this study was an ictus dated back at least 2 months. In the other studies blood lipids and Lp(a) serum values were estimated in intervals after stroke ranging from 4 weeks11 to 3 months9 or between 26 and 28 months in chronic ischemic stroke patients.12 Thus, one would conclude that the Lp(a) serum concentrations as estimated in our study were not affected by the selected time point of the blood collection.
All 553 subjects taking part in this study underwent a noninvasive investigation of their extracranial carotid arteries. The portion of subjects with Lp(a) serum concentrations >20 mg/dL increased strongly with carotid artery occlusion, indicating that Lp(a) is an important marker for vessel wall narrowing. In fact, it was reported recently that Lp(a) serum levels were elevated in 492 asymptomatic subjects with preclinical atherosclerosis, ie, intima-media wall thickening in the extracranial carotid arteries, diagnosed noninvasively with B-mode ultrasonography.7 Furthermore, Lp(a) was identified in this study as an even better marker for stroke than the sonography score of the carotid arteries. This is of particular importance because Lp(a) serum levels are relatively constant throughout life, and their estimation can be included in routine laboratory measurements, whereas the extent of carotid atherosclerotic plaques increases with age,5 and its assessment requires a sonographic investigation.
In a recent report, Sandholzer et al38 showed that the
apo(a) isoforms predict risk for coronary heart disease in
several populations. This encouraged us to study the frequency of
apo(a) isoforms in all subjects investigated. The portion of small
apo(a) isoforms (molecular weight 580 kD) in our stroke patients
(42.65%) and subjects with a sonography score >0 (52.3%) was
comparable with the values obtained with patients suffering from
coronary heart disease (Tyrolean, 49.0%; Welsh, 48.5%; and
German, 39.6%).38 The frequency of small apo(a) isoforms
in ischemic stroke patients versus control subjects as well as
in subjects having a sonography score >0 versus those with a
sonography score of 0 were significantly higher. Regarding apo(a)
isoform distribution and carotid atherosclerosis, our
results are in agreement with a recent investigation on patients
suffering from end-stage renal disease.39 However, in
a study on subjects with asymptomatic
atherosclerosis, Lp(a) serum concentration but not the
apo(a) phenotype was found to be an independent predictor of
the case-control status.40 This difference is probably
due to the fact that in that study only asymptomatic
subjects with preclinical carotid atherosclerosis were
compared with subjects free of carotid atherosclerosis.
Yet, in our study a completely different population was investigated,
48% of whom were stroke patients. During the preparation of this
report, an article was published on the influence of the apo(a)
polymorphism on Lp(a) serum concentration in Spanish patients with
ischemic cerebrovascular disease.41 In that report
Lp(a) serum levels were significantly higher in patients with the S2
and S4 phenotype compared with control subjects. In our study
the patients' Lp(a) serum levels were higher in all phenotype
categories except S5 compared with control subjects. The influence of
race, another classification mode of stroke used, and the fact that a
smaller and only male population was investigated in the Spanish study
could account for the divergent results. These differences are probably
also responsible for the observation of similar apo(a)
phenotype frequencies in patients and control subjects in the
cited study.41 Furthermore, as a result of the low Lp(a)
serum concentrations of the control subjects we obtained a high
percentage of the null phenotype in our control group.
The eminent role Lp(a) seems to play in atherogenesis is probably due to the dual way in which this lipoprotein appears to function. Experiments with transgenic mice expressing the human apo(a) gene showed that the presence of apo(a) leads to a massive lipid deposition in the artery wall.42 Regarding a possible impairment of fibrinolysis by Lp(a)43 44 —several copies of kringle IV homologous to plasminogen are present in apo(a)1 —a recent clinical investigation indicated that apo(a) hampers intrinsic fibrinolysis in vivo. Survivors of myocardial infarction who failed to recanalize the infarct artery had significantly higher plasma Lp(a) concentrations than patients with a patent infarct artery.45
Atherogenesis is a multifunctional pathological process that also takes place in humans with low Lp(a) serum levels or in animals not expressing the apo(a) gene. However, the results presented here support the assumption that elevated Lp(a) serum concentrations as well as low-molecular-weight apo(a) isoforms are strongly associated with an acceleration of the atherosclerotic process in the carotid arteries and the event and severity of stroke.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by the Österreichischer Fonds zur Förderung der wissenschaftlichen Forschung (project P8271-Med).
Received April 10, 1995; revision received July 3, 1995; accepted July 11, 1995.
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