© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Major Reduction in Plasma Lp(a) Levels During Sepsis and Burns
From the Department of Medicine (V.M., P.N.), Surgical Intensive Care Unit (M.M.B., C.C., R.C.), Institute of Physiology (L.T.), and Medical Policlinic (R.D.), CHUV University Hospital, Lausanne, Switzerland, and the Northwest Lipid Research Laboratories (S.M.M.), Seattle, Wash.
Correspondence to Vincent Mooser, MD, Department of Medicine, CHUV University Hospital, BH 19-135, CH-1011 CHUV Lausanne, Switzerland. E-mail vincent.mooser{at}hola.hospv.ch
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Abstract |
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Abstract—Plasma levels of lipoprotein(a) [Lp(a)], an atherogenic particle, vary widely between individuals and are highly genetically determined. Whether Lp(a) is a positive acute-phase reactant is debated. The present study was designed to evaluate the impact of major inflammatory responses on plasma Lp(a) levels. Plasma levels of C-reactive protein (CRP), low density lipoprotein cholesterol, Lp(a), and apolipoprotein(a) [apo(a)] fragments, as well as urinary apo(a), were measured serially in 9 patients admitted to the intensive care unit for sepsis and 4 patients with extensive burns. Sepsis and burns elicited a major increase in plasma CRP levels. In both conditions, plasma concentrations of Lp(a) declined abruptly and transiently in parallel with plasma low density lipoprotein cholesterol levels and closely mirrored plasma CRP levels. In 5 survivors, the nadir of plasma Lp(a) levels was 5- to 15-fold lower than levels 16 to 18 months after the study period. No change in plasma levels of apo(a) fragments or urinary apo(a) was noticed during the study period. Turnover studies in mice indicated that clearance of Lp(a) was retarded in lipopolysaccharide-treated animals. Taken together, these data demonstrate that Lp(a) behaves as a negative acute-phase reactant during major inflammatory response. Nongenetic factors have a major, acute, and unexpected impact on Lp(a) metabolism in burns and sepsis. Identification of these factors may provide new tools to lower elevated plasma Lp(a) levels.
Key Words: lipoprotein(a) • apolipoprotein(a) • sepsis • burns • inflammation
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Introduction |
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Elevated plasma levels of lipoprotein(a) [Lp(a)]1 are associated with the premature development of atherosclerosis.2 3 Plasma levels of Lp(a) vary widely between individuals4 and are largely determined by sequences within the locus encoding apolipoprotein(a) [apo(a)],5 6 the highly polymorphic glycoprotein that is attached to apolipoprotein B (apoB) of LDL to form Lp(a).1 Only a limited number of physiological factors (such as estrogens,7 testosterone, growth hormone, or thyroid hormone), disease conditions (such as renal failure8 9 10 or some peroxisomal disorders11 ), or environmental agents (such as alcohol,12 nicotinic acid, or HIV-1 protease inhibitors13 ) have been shown to modify plasma Lp(a) levels.14 Furthermore, changes associated with these factors are usually progressive (over a period of weeks) and limited in their amplitude (in the range of
50% to 150%). On the basis of cross-sectional studies15 and on serial measurements of plasma Lp(a) levels after myocardial infarction16 or surgery,17 it has been proposed that Lp(a) is a positive acute-phase reactant; ie, plasma levels of Lp(a) increase during inflammation. Conceptually, the hypothesis is appealing because after injury, Lp(a) may deliver lipids necessary to the wound-healing process to tissues that have the highest requirements for such substrates. Accordingly, Lp(a) may provide some survival advantage.18
Because the impact of major inflammatory response on Lp(a) had not been
examined, we performed in the present study serial measurements of
plasma levels of Lp(a) in subjects admitted to the intensive care unit
(ICU) for sepsis or extensive burns, 2 conditions characterized by a
pronounced systemic inflammatory response syndrome (SIRS), low plasma
levels of total, HDL, and LDL
cholesterol,19 20 and high concentrations of
cytokines, such as tumor necrosis factor-
(TNF-)21 and interleukin (IL)-6.22 To our
surprise, we observed a pronounced reduction in plasma Lp(a) levels
that closely paralleled the changes in LDL cholesterol
levels.
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Methods |
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Clinical Study
This part of the study enrolled patients aged 18 to 70 years admitted to the ICU for sepsis, as defined by the American College of Chest Physicians/Society of Critical Care Medicine,23 or extensive burns (>20% body surface area). The Sepsis-Related Organ Failure Assessment (SOFA) score24 was applied to evaluate the severity of sepsis and the number of organs with failure. Patients in shock were excluded. Plasma samples were collected within 24 hours of admission and daily for the first 5 days and then every second day until day 11. Twenty-four–hour urine samples were collected every second day. Survivors were contacted after 16 to 18 months for a follow-up blood collection. The protocol was approved by the local ethics committee, and a consent form was obtained from each participant or from a close relative.
All measurements were performed within 3 months of collection on plasma samples that had been stored at -20°C and had not been thawed previously. Concentrations of Lp(a) in plasma were determined by using mouse monoclonal antibodies of well-defined specificity (IgG-a6 and IgG-a4025 ). This assay, which has the advantage of being insensitive to the size of the apo(a) isoforms, was imported from Northwest Research Lipid Laboratories and implemented in our laboratory, as described.13 26 The same calibrator and quality controls were used for measurements of Lp(a) in plasma samples collected in the study period and the follow-up period. Coefficients of variations for the assay were 11% for plasma levels of Lp(a) <5 mg/dL, 8% for values between 5 and 50 mg/dL, and 12% for levels >50 mg/L. Free apo(a) levels in plasma and in urine were examined by using mouse monoclonal antibodies IgG-a6 and IgG-a5, as described.27 28
Variables were examined by paired t tests or nonparametric tests [for plasma Lp(a) levels].
Clearance Studies in Mice
Female NMRI mice weighing 30 g were injected
intraperitoneally with lipopolysaccharide
(LPS, Sigma Chemical Co) at a dose of 33 mg/kg (n=5) or vehicle (n=5).
This dose was selected to ensure that the majority of mice experienced
sepsis and survived for at least 16 hours.29 Fourteen
hours later, the mice were injected intravenously with a
total of 170 µL of Lp(a)-containing serum that had been collected
from mice expressing a human apo(a) transgene (+/-) and human apoB-100
(+/+) on an LDL-receptor knockout background (-/-).30
These Lp(a)-transgenic mice were not suitable for expression studies,
because the apo(a) transgene in these mice is driven by the mouse
transferrin promoter, not the apo(a) promoter. A total of 50 µL of
blood was collected 90 seconds and 1, 2, 3, 4, and 5 hours after the
injection of Lp(a)-containing serum. Injections and blood collections
were performed on transiently anesthetized mice exposed to
methoxyflurane. Blood glucose levels were measured at each time point
with a Bayer glucometer. Serum was isolated, and Lp(a) was quantified
as described above. In addition, serum Lp(a) was examined by
immunoblot analysis on 5% SDS-PAGE, with the use
of horseradish peroxidase–conjugated mouse monoclonal antibody IgG-a5,
as described.28
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Results |
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Nine subjects (7 male and 2 female) with sepsis (SOFA scores ranging from 4 to 14, mean±SEM 8.3±1.3), aged 19 to 68 (54±5) years, were included in the study (Table
, subjects S-1
to S-9). Sepsis was associated with acute respiratory distress syndrome
(subjects S-1, S-4, and S-7), gastrointestinal surgery (subjects S-2,
S-5, S-8, and S-9), heart surgery (subject S-3), or multiple injury
(subject S-6). At entry, the number of organ failures ranged from 2 to
4 (3.1±0.3 organs). None of the patients presented signs of
hepatic failure. The hematocrit averaged 31.7±1.1%. A pronounced
inflammatory response was observed that was characterized by the
presence of plasma C-reactive protein (CRP) levels >80 mg/L (214±27
mg/L), elevated leukocyte counts (20.9±4.3 g/L), total
cholesterol levels <3.5 mmol/L (1.73±0.21
mmol/L), and very low plasma LDL cholesterol levels
(0.61±0.16 mmol/L). A close correlation was observed between
plasma levels of total cholesterol and albumin
(r=0.47, P<0.01). The distribution of plasma
Lp(a) levels was markedly skewed toward low values (median 1.6
mg/dL).
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Septic patients were followed for 5 to 11 (8.8±0.9) days. Subject S-2 died at day 5, whereas subjects S-4 and S-5 died 12 and 24 days after admission to the ICU, respectively. In these subjects, plasma CRP levels remained >150 mg/L during the study period, whereas concentrations of LDL and Lp(a) remained very low (<0.7 mmol/L and <2.5 mg/dL, respectively).
Six septic subjects survived. Four of them were contacted, and blood
was drawn 16 to 18 months after the study period (subjects S-1, S-3,
S-6, and S-9). The individual profiles in plasma levels of CRP, LDL
cholesterol, and Lp(a) are presented in Figure 1. A sharp transient elevation in plasma
CRP levels (from 194±31 to 316±39 mg/L, P<0.001; Figure 1, top panels) was observed (except for subject S-8), with
plasma CRP levels being still markedly elevated at completion of the
study period (114±19 mg/L). CRP was undetectable (ie, <5 mg/L) in
plasma samples collected in the follow-up period. Changes in plasma CRP
levels were mirrored by plasma LDL cholesterol levels (from
0.84±0.22 to 0.30±0.14 mmol/L, P<0.001; Figure 1, middle panels). Strikingly enough, plasma levels of LDL and
Lp(a) (bottom panels) evolved closely in parallel in all 6 subjects,
with a 44% reduction in plasma Lp(a) levels observed within days.
Follow-up reference values were 5- to 15-fold (9.4±2.0) higher than
the nadir observed during the study period, consistent with a
80% to 95% reduction in plasma Lp(a) levels during sepsis.
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To determine whether the changes in plasma Lp(a) levels were due to fragmentation of apo(a), we serially quantified the concentration of free apo(a) in plasma28 and urine.27 31 Plasma levels of free apo(a) and Lp(a) evolved in parallel, with a decline from 0.13±0.05 mg/dL at entry to 0.09±0.02 mg/dL at the peak of inflammatory response and 0.12±0.04 mg/dL at completion of the study (P=NS). Respective values for urinary apo(a) were 15±8, 12±5, and 14±7 ng/µmol of creatinine. Taken together, these data indicated that the transient reduction in plasma Lp(a) levels observed in critically ill patients was not due to fragmentation of apo(a) in plasma or to an increased excretion of apo(a) into urine.
To examine whether the acute reduction in plasma Lp(a) levels was
specific to sepsis, we examined an additional set of 4 patients
admitted to the ICU for SIRS elicited by extensive burns (Table
,
subjects B-1 to B-4). Within days, plasma CRP levels increased from
26±14 to 173±5 mg/L (P<0.001), whereas LDL
cholesterol levels decreased from 2.72±0.13 to
1.33±0.10 mmol/L (P<0.001). In parallel, plasma
concentrations of Lp(a) declined from 0.6 to <0.1 mg/dL in subject
B-1, from 8.1 to 3.4 mg/dL in subject B-2 (follow-up reference value
15.6 mg/dL), from 38.0 to 16.9 mg/dL in subject B-3, and from 0.2 to
<0.1 mg/dL in subject B-4. No increase in plasma levels of free apo(a)
or urinary apo(a) was observed. Taken together, these data indicated
that the changes in plasma Lp(a) levels during sepsis were not specific
for this condition but were most probably associated with the major
inflammatory response elicited by both SIRS and sepsis.
The major decline in plasma Lp(a) levels observed during sepsis and
SIRS may be due to accelerated clearance of these particles or reduced
synthesis. To gain insight into the mechanism responsible for this
phenomenon and because of difficulties in performing
metabolic studies on Lp(a) in humans, we next performed
clearance studies in mice. A total of 170 µL of Lp(a)-containing
serum harvested from Lp(a)-transgenic mice was injected
intravenously into mice previously treated with LPS (n=5)
or vehicle (n=5). LPS-pretreated animals were prostrated, and their fur
had an unhealthy appearance. In addition, blood glucose levels were
<3.0 mmol/L (2.3±0.2 mmol/L) in LPS-pretreated mice at the
initiation of clearance studies compared with >6.8 mmol/L in
vehicle-pretreated mice (8.3±0.6 mmol/L, P<0.001), a
finding consistent with severe sepsis.32
Blood was collected 90 seconds and 1, 2, 3, 4, and 5 hours after
injection, and serum levels of Lp(a) were quantified. In
vehicle-pretreated mice, serum levels of Lp(a) decreased progressively
from 1.09±0.07 mg/dL at baseline (90 seconds) to 0.41±0.02 mg/dL
after 5 hours, with a half-life of 3.7±0.2 hours (Figure 2A). In contrast, plasma Lp(a) levels in
LPS-pretreated animals increased between baseline (1.05±0.06 mg/dL)
and 1 hour to a higher level (1.25±0.08 mg/dL, P<0.05)
than the one observed at baseline in vehicle-pretreated animals. This
observation was consistent with a profound
hemodynamic collapse and poor mixing of injected serum
within a reduced blood volume.33 In addition,
clearance of Lp(a) was slower in LPS- than in vehicle-treated mice,
with an estimated half-life of 6.4±0.4 hours (P<0.001
versus vehicle-pretreated mice). To determine whether fragmentation of
Lp(a) was present, serum samples were subjected to
immunoblot analysis, and a
representative result is illustrated in Figure 2B. The injected material is examined in the left lane (lane S).
In addition to full-length apo(a) (top band), additional smaller bands
of lesser intensity are detectable, which are specific to serum,
because such bands were not visible when plasma from Lp(a)-transgenic
mice was analyzed (data not shown). No fragmentation of apo(a)
was observed during the time points examined.
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Discussion |
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Plasma concentrations of Lp(a) vary widely between individuals but are generally only minimally modifiable within 1 given subject. In the present study, we demonstrate that in critically ill subjects with intense inflammatory response elicited by sepsis or extensive burns, plasma levels of Lp(a) are markedly, acutely, and transiently reduced. Accordingly, nongenetic factors have a major unexpected impact on plasma Lp(a) levels in these conditions.
The acute reduction in plasma levels of Lp(a) during sepsis and burns
may be due to inflammation-related changes in Lp(a)
metabolism, to liver dysfunction, to hemodilution, or to a
combination of these factors. None of the patients examined in the
present study exhibited signs of acute liver failure. In addition,
hematocrit levels in septic patients remained remarkably stable
throughout the study period (31.7±1.1% at entry versus 30.1±1.5% at
the peak of inflammatory response, P=NS). Accordingly, our
data demonstrate that the decline in plasma Lp(a) levels observed
during sepsis or burns is mostly mediated by the intense inflammatory
response triggered by these 2 conditions. As such, Lp(a) can be
considered to be a negative acute-phase reactant.34
Interestingly enough, an 2-fold decrease in plasma levels of apo(a)
was recently reported in YAC-apo(a) transgenic mice challenged
with turpentine, which induced a marked inflammatory
response,35 and this was associated with a 3-fold
reduction in the amount of apo(a) transcripts in the liver.
Inflammation may be associated with an accelerated removal of Lp(a) from the circulation or reduced synthesis by the liver. The mechanism by which Lp(a) is cleared from the circulation is not yet fully elucidated. Lp(a)-derived fragments of apo(a) have been identified in human plasma28 and are the likely source of the smaller apo(a) fragments present in urine.27 31 In the present study, plasma concentrations of free apo(a), which comprises apo(a) fragments and full-length apo(a) not bound to LDL particles, and urinary apo(a) levels remained unchanged during the study period, indicating that the decline in plasma Lp(a) levels during sepsis and burns was probably not due to accelerated fragmentation of apo(a) in plasma. This observation is in accord with our previous observation, wherein we showed that surgery necessitating cardiopulmonary bypass was not accompanied by a rise in plasma levels of free apo(a) or urinary apo(a), despite a marked increase in plasma concentrations of CRP and immunoreactive polymorphonuclear elastase,26 and is also in accord with the present clearance studies, which showed that the size of the apo(a) glycoprotein remained unchanged in septic mice injected with Lp(a)-containing serum. Data from these clearance studies in mice must be interpreted with caution, though, because mice do not have apo(a), and Lp(a) particles may have a conformation different from that in humans.
In the present study, plasma levels of Lp(a) and LDL evolved closely in parallel. It is highly unlikely that the decline in plasma concentrations of LDL and Lp(a) was due to increased activity of the LDL receptor, because statin-mediated upregulation of the LDL receptor has only minimal, if any, effect on plasma levels of Lp(a).36 However, we cannot formally rule out the possibility that an LDL receptor–independent pathway responsible for the clearance of LDL and Lp(a) particles is activated during sepsis and burns or that the parallel evolution in plasma levels of LDL and Lp(a) is coincidental. However, these possibilities are unlikely.
Taken together, the absence of fragmentation of apo(a) in plasma, the parallel evolution of plasma Lp(a) and LDL levels, and the retarded clearance of Lp(a) in septic mice, coupled with the reduced expression of the apo(a) gene in YAC-apo(a) mice challenged with turpentine, provide evidence for a marked reduction in the production of LDL and Lp(a) particles during sepsis and burns. Reduced production of Lp(a) during sepsis may be due to amounts of LDL that are insufficient to form Lp(a) particles (as is the case in abetalipoproteinemia) and/or to factors acting in a trans fashion that inhibit the production of LDL and Lp(a) particles.
Abetalipoproteinemia is a recessive disorder that is due to mutations within the gene encoding microsomal transfer protein and is characterized by very low, or undetectable, concentrations of apoB in plasma.37 In these situations, Lp(a) levels are usually low or very low38 because of the inability of apo(a) to complex with apoB at the surface of the hepatocyte,39 40 so that part of apo(a) circulates free of LDL.28 38 In our particular situation, however, no increase in plasma concentrations of free apo(a) was observed. Furthermore, the decline in plasma Lp(a) levels was observed in all subjects, irrespective of their plasma concentration of Lp(a) at entry, whereas if the amount of LDL available would be limiting for the production of Lp(a), one would have expected this decline to be more pronounced in subjects with elevated Lp(a) levels at entry. Taken together, our data rather suggest that common factors acting in a trans fashion inhibit the production of LDL and Lp(a).
The elements that regulate the expression of the apo(a) gene are not
fully elucidated. However, cytokines, which play a key role in
inflammation and sepsis,34 have been shown to have an
impact on the expression of the apo(a) gene. Indeed, in vitro studies
on primary cultures of monkey hepatocytes have shown that
IL-6 stimulates, whereas transforming growth factor-ß1 and TNF-
inhibit, the expression of the apo(a) gene.41 Accordingly,
it is conceivable that in SIRS and sepsis, these latter
cytokines predominate, so that the production of Lp(a)
is reduced, whereas in milder inflammatory states, as in the period
after myocardial infarction or surgery,15 16 17 the
stimulatory effect of IL-6 overrides the effect of
inhibitory cytokines so that an increase in plasma
levels of Lp(a) is observed. Interestingly enough, TNF-, IL-1ß,
and IL-6 have been shown to decrease the amount of microsomal transfer
protein mRNA levels,42 whereas TNF-, IL-1ß, and IL-6
decrease the amount of apoB in the medium when HepG2
cells43 or human fetal
hepatocytes44 are exposed to these
cytokines. Accordingly, these cytokines may well
explain the parallel decline in plasma concentrations of Lp(a) and LDL
during major inflammatory response.
In conclusion, this is the first observation that Lp(a) behaves as a negative acute-phase reactant in humans. In sepsis and burns, a decline in plasma concentrations of Lp(a) was observed that reached a nadir lower than that observed with any intervention in adults (other than liver transplantation). Evidence is provided that the parallel decline in plasma concentrations of LDL and Lp(a) is due to the effect of various cytokines that inhibit the production of both particles. A better understanding of the molecular mechanisms responsible for reduced levels of Lp(a) in SIRS and sepsis may unravel novel targets by which elevated levels of Lp(a) in plasma may be lowered.
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Acknowledgments |
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This study was supported by the Swiss Foundation for Scientific Research (SCORE grant No. 32-44471.95 to Dr Mooser), the Fondation Placide Nicod, and the Fondation Botnar. The authors wish to thank Vincent Lenain and Gilda Crespell for excellent technical assistance, Luca Liaudet and François Feihl for their help in conducting studies in mice and for their generous gift of LPS, Gérard Waeber and Vincent Jomini for helpful discussions, Helen Hobbs for careful reading of the manuscript, Pierre Fontana for his contribution to the statistical analysis, and the nursing staff of the surgical ICU for their help in collecting samples.
Received September 13, 1999; accepted October 7, 1999.
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