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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 63:122-126 (2008)
© 2008 The Gerontological Society of America

Plasma Apolipoprotein CI Protects Against Mortality From Infection in Old Age

Jimmy F. P. Berbée, Simon P. Mooijaart, Anton J. M. de Craen, Louis M. Havekes, Diana van Heemst, Patrick C. N. Rensen and Rudi G. J. Westendorp

1 Department of Biomedical Research, TNO-Quality of Life, Gaubius Laboratory, Leiden, The Netherlands. Departments of
<2 General Internal Medicine, Endocrinology and Metabolic Diseases, 3 Gerontology and Geriatrics, and 4 Cardiology; Leiden University Medical Center, The Netherlands.

Address correspondence to Jimmy F. P. Berbée, PhD, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, C4-R, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: J.F.P.Berbee{at}lumc.nl


   Abstract
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Methods
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 Discussion
 References
 
The high-density lipoprotein (HDL) constituent apolipoprotein CI (apoCI) protects mice against mortality in bacterial sepsis. We assessed whether high plasma apoCI levels protect against mortality from infection in humans. We determined plasma levels of apoCI, lipids, and C-reactive protein in 85-year-old participants of the prospective population-based Leiden 85-Plus Study (n = 561). Participants were followed for specific causes of death. High apoCI levels were associated with 40% reduced risk of mortality from infection (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.42–0.86; p =.005) for every increase of 1 standard deviation in apoCI level. A similar association was observed for high HDL cholesterol (HR, 0.65; 95% CI, 0.46–0.94; p =.022), but not for LDL cholesterol, triglycerides, and C-reactive protein levels. The association of apoCI was independent of HDL cholesterol, as multivariate analysis did not alter the association for apoCI (HR, 0.63; 95% CI, 0.44–0.90; p =.013), whereas for HDL cholesterol significance was lost. We conclude that high apoCI levels are associated with reduced mortality from infection, in line with experimental evidence in rodents.

Key Words: Apolipoprotein CI • High-density lipoprotein • Infection

APART from regulating lipid metabolism, evidence accumulates that lipoproteins are also involved in the outcome of infectious disease (1–5). In particular, high levels of high-density lipoprotein (HDL) have been associated with increased protection against infection-related mortality (2,4,5). Experimental studies in rodents suggest that not the lipid content of the lipoproteins, but rather the associated surface apolipoproteins, are responsible for the protective effect against infection (6–14). Recently, by using genetically engineered mice that either lack apolipoprotein CI (apoCI) or overexpress apoCI, we showed that apoCI protected against mortality in bacterial sepsis (7). The relationship between plasma levels of apoCI and infectious disease mortality in humans has not yet been studied.

ApoCI predominantly circulates as a surface component of HDL at a relatively high plasma concentration of about 6–10 mg/dL (15–17). At 6.6 kd, it is the smallest apolipoprotein known to date. Studies in vitro (18–21) and in vivo (22) show that apoCI modulates the activity of plasma factors involved in HDL metabolism such as cholesteryl ester transfer protein (CETP) (19,22), lecithin cholesterol acyltransferase (LCAT) (21), and hepatic lipase (HL) (18,20). Studies with apoCI-deficient mice indeed showed that apoCI expression correlated positively with HDL cholesterol levels (23). However, the fact that administration of lipid-free apoCI enhanced a beneficial proinflammatory host response toward bacterial products in vivo, without altering HDL cholesterol levels (7), strongly suggests that the effect of apoCI on infection-related outcome is independent of HDL cholesterol levels.

Here we analyzed whether, in humans, high plasma apoCI levels protect against mortality from infection. To this end, we determined the plasma apoCI, lipid, and C-reactive protein (CRP) levels, and mortality from infection within the Leiden 85-Plus Study, a prospective, population-based follow-up study of elderly persons aged 85 years. Within this age category, 17% of deaths occur due to infection-related causes. Our findings reveal that, in the population at large, high apoCI levels indeed are associated with reduced mortality from infection.


   METHODS
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Participants
Between September 1, 1997, and September 1, 1999, a total of 705 inhabitants of the community of Leiden, The Netherlands, reached the age of 85 years. Among these 85-year-old persons, we initiated a follow-up study to investigate determinants of successful aging. There were no selection criteria on health or demographic characteristics. The response rate was 87%; a total of 599 individuals participated (24). There were no significant differences in various demographic characteristics between the 599 respondents and the source population. Of the 599 participants in the cohort, 38 refused to provide a blood sample, yielding a total number of 561 participants for the present study. The Medical Ethical Committee of the Leiden University Medical Center approved the study, and informed consent was obtained from all participants.

Plasma Parameters
At baseline, participants were visited twice at their place of residence within 1 month after the participant's 85th birthday. All (nonfasting) blood samples were collected before 11 AM. Plasma apoCI levels were determined using a human apoCI-specific sandwich enzyme-linked immunosorbent assay (ELISA) as described previously (25). In short, a polyclonal goat anti-human apoCI antibody (Academy Biomedical Co., Houston, TX) was coated onto Costar medium binding plates (Corning, Inc., New York, NY) and incubated with diluted human plasma (dilution 1:150,000). Subsequently, the wells were incubated with horseradish peroxidase (HRP)-conjugated polyclonal goat anti-human apoCI antibody (Academy Biomedical Co.), and finally HRP was detected by incubation with tetramethylbenzidine (Organon Teknika, Boxtel, The Netherlands). Plasma from C57BL/6 mice spiked with human apoCI (Labconsult, Brussels, Belgium) was used as a standard.

Plasma levels of total cholesterol, HDL cholesterol, triglycerides (TG), and CRP were analyzed on fully automated computerized analyzers (Hitachi 747 and 911; Hitachi, Ltd, Tokyo, Japan). The level of low-density lipoprotein (LDL) cholesterol was estimated by the Friedewald equation (LDL cholesterol [mmol/L] = total cholesterol – HDL cholesterol – [TG/2.2]), whereby participants with a TG concentration >443 mg/dL (5 mmol/L) were excluded (n = 5).

Causes of Death
For the analyses presented in this research, all participants were followed for mortality until April 1, 2004. The date of death was obtained from the civic registries. Shortly after civic registries reported the death of a participant, the general practitioner or nursing home physician was interviewed to determine the cause of death by means of a standardized questionnaire. Two senior specialists of internal medicine, unaware of the outcomes of the analyses, in 2004 reviewed the causes of death and classified each death into primary causes of death according to the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). Cardiovascular mortality was classified as ICD codes I00–I99, mortality from infection as ICD codes A00–B99 and J10–J18, and cancer as C00–D48. All other ICD codes were grouped as other cause of mortality. In six participants, the cause of death could not be established.

Statistical Analyses
Plasma levels of apoCI and total, LDL, and HDL cholesterol were normally distributed and are presented as means. Plasma levels of TG and CRP were not normally distributed and are presented as medians with interquartile range to assess distribution in the total population and as geometric means to compare means between groups. Individuals with undetectable CRP levels were attributed half of the minimal detection limit (0.25 mg/L) to allow log transformation. Differences in levels of these lipids were calculated using sex-adjusted linear regression. Mortality risks were estimated using Cox proportional hazards models, which were all adjusted for gender. All calculations were performed using SPSS 12.0.1, and Kaplan–Meier curves were generated using STATA 9 SE.


   RESULTS
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Baseline Characteristics and Lipid Correlations
The baseline characteristics of the study population are listed in Table 1. The mean plasma apoCI concentration was 6.68 ± 2.07 mg/dL, comparable with concentrations reported in other populations (15–17).


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  		Table 1. Baseline Characteristics of Study Participants.

 
Correlation of plasma apoCI levels with all classical lipid parameters revealed a strong and positive association between plasma apoCI levels and levels of total, LDL, and HDL cholesterol, and TG (Table 2; all p <.001). In addition, we found a negative association between plasma apoCI levels and plasma CRP levels (Table 2; p <.01


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  		Table 2. Plasma Levels of Lipid Parameters and CRP According to Quartiles of Plasma ApoCI Levels.

 
Mortality
Because our previous experimental studies in mice showed that high plasma apoCI levels are associated with reduced mortality from infection (7), we calculated the risk of mortality from infection dependent on the plasma levels of apoCI. Of the 561 participants, 48 (17%) died due to an infection-related cause. As shown in Figure 1, participants with high plasma levels of apoCI (above the median) had a significantly reduced cumulative risk of mortality from infection as compared with participants with low plasma apoCI levels (below the median). In a sex-adjusted Cox proportional hazards model, the risk of mortality decreased by a factor of 0.60 (95% confidence interval [CI], 0.42–0.86; p =.005) for every increase of 1 standard deviation in apoCI level.


Figure 01
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  		Figure 1. Cumulative mortality from infection dependent on plasma apolipoprotein CI (apoCI) levels. Kaplan–Meier curves for mortality from infection for participants with high (above median) and low (below median) plasma apoCI level. The p value indicates statistical significant in a sex-adjusted Cox proportional hazards model

 
To determine whether high levels of apoCI were specifically associated with reduced mortality from infection, and were not a general reflection of good health, we calculated risk of mortality from different causes dependent on plasma apoCI levels (Table 3). The risk of all-cause mortality decreased by a factor of 0.79 (95% CI, 0.69–0.91; p =.001) for every increase of 1 standard deviation in plasma apoCI level. In contrast to the strong association of plasma apoCI levels with mortality from infection, the association with cardiovascular disease mortality was weaker (0.79; 95% CI, 0.64–0.99; p =.036). No significant associations between plasma apoCI levels and mortality from cancer (0.88; 95% CI, 0.62–1.27) or from other causes (0.88; 95% CI, 0.67–1.16) were found.


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  		Table 3. Risk of All-Cause Mortality and Mortality from Specific Causes Dependent on Plasma ApoCI Levels.

 
When analyzing the association of other plasma parameters with mortality from infection, we found that high levels of CRP were not significantly associated with an increased risk of mortality from infection (1.23; 95% CI, 0.99–1.53). When entered into a multivariate model, levels of CRP did not affect the observed association of high levels of apoCI with reduced risk of mortality from infection (0.61; 95% CI, 0.42–0.87). Of the classical lipid parameters, in particular HDL cholesterol has been associated with reduced mortality from infection (2,4,5). In our population, apart from plasma apoCI, only HDL cholesterol level was significantly associated with mortality from infection (0.65; 95% CI, 0.46–0.94; p =.022), and not LDL cholesterol (0.77; 95% CI, 0.57–1.05) or TG (0.90; 95% CI, 0.67–1.20). In addition, because most of the circulating apoCI can be found on the surface of HDL in normolipidemic participants (i.e., 90%–95%) (15), we show here that plasma apoCI levels were positively correlated with HDL cholesterol levels (Table 2), we investigated whether the reduced risk of mortality from infection with high apoCI levels was dependent on the association of apoCI with HDL cholesterol. When apoCI and HDL cholesterol were simultaneously entered into the model, the protective effect of apoCI on mortality from infection remained similar (0.63; 95% CI, 0.44–0.90; p =.013), whereas for HDL cholesterol the protective effect slightly decreased and significance was lost (0.72; 95% CI, 0.49–1.04; p =.074). Moreover, there was no significant interaction of the risk of mortality from infection associated with high levels of apoCI and the risk of mortality from infection associated with high levels of HDL cholesterol (data not shown; p =.681).


   DISCUSSION
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The results of the present prospective population-based study show that, in old age, high plasma apoCI levels are strongly associated with lower risk of mortality from infection. The protective effect of apoCI was specific for mortality from infection and independent of HDL cholesterol levels. Our previous experimental studies in which we showed that apoCI was protective in a murine bacterial sepsis model (7) can thus be extrapolated to humans.

Our results show that, within the Leiden 85-Plus Study, participants with high plasma apoCI levels at baseline are less prone to mortality from infection during a 5-year follow-up period. To our knowledge, there is only one report published on the relationship between apoCI and infection in humans, which showed that HDL was virtually depleted from apoCI during human sepsis (26), supportive for a role of apoCI in human infection. We also found total plasma levels of apoCI to be decreased in septic patients, and that this decrease was selective as compared with levels of lipoprotein lipids (Berbée JFP, Havekes LM, Rensen PCN, unpublished data, 2006).

From our previous study (7), we have concluded that high plasma levels of apoCI effectuate a more efficient killing of invading microorganisms, by virtue of an increased sensitivity to respond to microorganisms and a concomitant increased proinflammatory host response. This increased host response results in a low bacterial load and, consequently, a reduced mortality risk. This host defense mechanism has been outstandingly described by Netea and colleagues (27), who stated that a proinflammatory cytokine response is crucial to surmount early phase bacterial infection, whereas in a late phase a high proinflammatory response is often harmful and may lead to tissue damage and organ failure. The mechanism behind the decrease in apoCI levels during sepsis is not yet understood. It may well be that the decrease in apoCI levels is a natural response of the host in an attempt to protect itself against an overwhelming cytokine response in a latter phase of infection, a speculation which is the subject of ongoing investigation.

Based on our current findings, the association of plasma apoCI levels with reduced mortality appears to be specific for mortality from infection, as apoCI levels are not significantly associated with cancer mortality and mortality from other causes, and we only found a weak association between apoCI levels and cardiovascular disease mortality. This weak association between reduced cardiovascular disease mortality and high apoCI levels is in line with the observed negative association between plasma CRP and apoCI levels in these participants. High circulating levels of CRP are a marker of chronic inflammation and cardiovascular disease (28,29). This intriguing association between high apoCI and low CRP levels is not yet understood. It may be related to an apoCI-mediated protection against the development of infections in general, thereby reducing the incidence of chronic inflammation during the life span and improving the general well-being as reflected by low plasma CRP levels. Another explanation for the observation that, in our population, high levels of apoCI are associated with decreased cardiovascular mortality is that plasma apoCI levels are positively associated with HDL cholesterol levels as we show in this study. The role of HDL in preventing cardiovascular disease has indisputably been established (30–32). ApoCI is able to directly increase HDL levels by modulation of several enzymes involved in HDL metabolism. ApoCI is the main endogenous inhibitor of CETP (19,22), an inhibitor of HL (18,20), and an activator of LCAT (21). These are all mechanisms shown to increase HDL cholesterol, indicating that high plasma apoCI levels could improve cardiovascular outcome via increasing HDL cholesterol levels.

The observed association of high levels of apoCI with decreased mortality from infection was independent of HDL cholesterol levels. A possible explanation for this finding is that a dual protective mechanism is exerted by apoCI and HDL. ApoCI acts proinflammatory and is involved in a more effective elimination of the pathogens in the early phase of infection, as discussed above, which may result in a reduced incidence of developing both nonfatal and fatal infections, and thereby may reduce the incidence of mortality from infection. In contrast, HDL as a whole acts primarily anti-inflammatory and may improve neutralization of microbial products such as lipopolysaccharide (LPS). This most likely does not result in a reduced incidence of developing (non)fatal infections, but HDL may be protective against mortality in the latter phase of infection by dampening the host's exaggerated inflammatory response toward the microbial products. Unfortunately, the design of the study allowed us to examine only the relationship of plasma apoCI and HDL levels with mortality from infection, and not with incidence of developing (non)fatal infections during follow-up. Another possibility is that this knowledge explains why high cholesterol levels (in particular, high HDL cholesterol levels) have previously been associated with a beneficial outcome of infection-related mortality in humans, a finding that is not yet properly understood (1–5). Accumulating evidence from primarily experimental studies shows that not the lipids (7,11,12), but rather the apolipoproteins located on the surface of lipoproteins determine the effect of the lipoproteins on the host response to infectious agents (9,11,33) and subsequent survival (8,10,11,13,14). Van der Poll and colleagues (12) showed that continuous infusion of Intralipid, a protein-free lipid emulsion, in humans did not affect inflammatory responses to LPS, the toxic component of gram-negative bacteria. Likewise, LDL receptor (LDLr) and LDLr-related protein double-deficient mice showed no altered inflammatory response after LPS stimulation as compared to wild-type mice (7), despite the severe hyperlipidemic phenotype in these mice (34). These findings indicate that lipids do not alter the infection-related host responses.

Our previous experiments in mice mainly focused on the role of apoCI in gram-negative bacterial sepsis (7), because we found that the C terminus of apoCI contains a highly conserved lysine-rich motif (i.e., KVKEKLK) involved in the avid binding of apoCI to LPS. We demonstrated that apoCI avidly bound LPS and stimulated the inflammatory response to LPS, thereby improving the antibacterial attack. However, in the population at large, in addition to gram-negative bacteria as one of the major contributors, also gram-positive bacteria and other infectious microorganisms such as fungi are responsible for infectious disease mortality (35). Because we show here that high plasma levels of apoCI protect against mortality from infection in the population at large, one may speculate that apoCI has a role in the host defense against microorganisms beyond that of gram-negative bacteria only.

A limitation of our study is that this finding cannot be directly extrapolated beyond this age group. The risk of high plasma apoCI levels for mortality from infection in middle age has yet to be determined. On the basis of official data from the Dutch Bureau of Statistics, 15% of men and 36% of women born between 1912 and 1914 actually survived until the age of 85 years. Therefore, this elderly population may be regarded as a minority of the total birth cohort and does not allow for extrapolation of our findings to other age groups. However, apparently a substantial portion of the total population reaches this age category, and an even larger portion will reach it in the near future. Blood samples were not drawn in a fasted state, which could have added random error to plasma apoCI and TG levels. However, all samples were drawn in the early morning, and it has been shown that apoCI levels in postprandial plasma do not differ from those in fasting samples (36). In addition, the triglyceride levels were similarly low as observed under fasting conditions (15), suggesting that the magnitude of random error is relatively small. A strength of our study is the specificity and sensitivity of the analyses due to the high incidence of fatal events during follow-up. Moreover, the data come from a population-based study without inclusion criteria on health and demographic characteristics.

Conclusion
High plasma apoCI levels protect against mortality from infection independent of HDL cholesterol. Our results support our previously proposed mechanism, in which apoCI functions as part of the innate host defense mechanism against invading microorganisms.


   Acknowledgments
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This study was supported in part by The Netherlands Organization for Scientific Research (NWO RIDE 014-90-001 to L.M.H., NWO VIDI 917-36-351 to P.C.N.R.), by the Leiden University Medical Center (Gisela Thier Fellowship to P.C.N.R.), by The Netherlands Heart Foundation (NHS 2005B226 to PCNR), and by the Dutch Ministry of Economic Affairs (IOP grant IGE01014 to R.G.J.W.).

This work was presented in part at the 8th Biennial Conference of the International Endotoxin Society, Kyoto, Japan, November 15–18, 2004 (abstract 17).


   Footnotes
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Decision Editor: Huber R. Warner, PhD

Received May 1, 2007

Accepted October 1, 2007


   References
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