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Clinical Chemistry 54: 139-146, 2008. First published November 16, 2007; 10.1373/clinchem.2007.094961
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Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
(Clinical Chemistry. 2008;54:139-146.)
© 2008 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Plasma Concentration of Heat Shock Protein 27 and Risk of Cardiovascular Disease: A Prospective, Nested Case-Control Study

Isabella Kardys1,8,a, Nader Rifai4,7, Olivier Meilhac12, Jean-Baptiste Michel12, Jose Luis Martin-Ventura11, Julie E. Buring1,2,6,10, Peter Libby5 and Paul M Ridker1,2,3,4,5,9,10

1 Center for Cardiovascular Disease Prevention and the Divisions of 2 Preventive Medicine and 3 Cardiology, Brigham and Women’s Hospital, Boston; 4 Harvard Medical School, Boston; 5 Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston; 6 Department of Epidemiology, Harvard School of Public Health, Boston; 7 Children’s Hospital Boston; 8 Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands; 9 Leducq Center for Molecular and Genetic Epidemiology; 10 Donald W. Reynolds Center for Cardiovascular Research; 11 Vascular Research Lab. Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; 12 INSERM Unit 698, Cardiovascular Hematology, Bio-Engineering and Remodeling, CHU X-Bichat, Université Paris 7, Paris, France.

aAddress correspondence to this author at: Department of Epidemiology & Biostatistics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Fax +31 10 4089382; e-mail i.kardys{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Heat shock protein 27 (HSP27) has been hypothesized to be a potential biomarker of atherothrombosis. However, no prospective studies have yet been performed to investigate the association between HSP27 plasma concentration and incident cardiovascular events among initially healthy individuals.

Methods: We evaluated plasma concentrations of HSP27 at baseline among 255 initially healthy participants in the Women’s Health Study who subsequently developed myocardial infarction, ischemic stroke, or cardiovascular death during a follow-up period of up to 5.9 years and among an equal number of women matched for age and smoking but who remained free of cardiovascular disease over the same time period.

Results: Overall, HSP27 plasma concentrations were inversely associated with age (Spearman correlation coefficient r = –0.258, P <0.001), but not with other established cardiovascular risk factors. Conditional logistic regression analysis showed no significant association of baseline HSP27 plasma concentration with future cardiovascular disease; the odds ratio for upper vs lower tertile of HSP27 concentration at baseline was 0.99 (95% CI 0.62–1.57, P for trend = 0.99).

Conclusion: In this prospective study of initially healthy women, baseline HSP27 plasma concentration was not associated with incident cardiovascular events.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Heat shock proteins (HSPs)1 are molecular chaperones that protect against stress stimuli including heat shock, oxidized LDL, mechanical stress, oxidants, and cytokine stimulation (1). Their primary function is to fulfill chaperoning activity: as new proteins are being produced by ribosomes, HSPs assist in correct folding of polypeptide chains into functional protein, and after a stress event, HSPs assist in refolding or degradation of damaged or denatured proteins (2).

HSPs are divided into several families according to molecular weight, including the 110, 90, 70, 60, and 40 kDa families, the small HSPs such as HSP27, and the HSP10 family. HSPs have been implicated in the pathogenesis of several disease processes. In relation to atherosclerosis, HSPs from the HSP60 and HSP70 families have been most widely investigated (1)(2). Recently, however, cardiovascular attention has also focused on HSP27, which is known to have chaperoning activity, to inhibit F-actin polymerization, to protect against apoptosis, and to be involved in the presentation of oxidized proteins to the proteosome degradation machinery (3). Specifically, using atherosclerotic carotid endarterectomy samples and control endarteries, we demonstrated that HSP27 secretion correlates negatively with atherosclerotic plaque complexity by comparing the complicated vs noncomplicated adjacent area from the same specimen and control endarteries. We also reported reduced HSP27 plasma concentrations in atherosclerotic patients compared with healthy individuals (4). Park et al. (5) used the same strategy but examined the tissue compartment, and also reported that HSP27 expression is increased in the normal-appearing vessel adjacent to atherosclerotic plaque compared with both the plaque core area and the reference arteries. By contrast, however, they reported that HSP27 plasma concentration was increased in acute coronary syndrome patients compared with normal individuals.

Taken together, these 2 recent studies raise the possibility that HSP27 may serve as a marker for atherothrombosis. To further evaluate this hypothesis, we performed a prospective, nested case-control study to examine whether baseline concentrations of HSP27 among initially healthy individuals are associated with future cardiovascular event rates.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study design
We used a prospective, nested case-control design within the Women’s Health Study, a recently completed randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer in US female healthcare professionals. Eligible participants were apparently healthy women, 45 years or older, who were free of self-reported cardiovascular disease or cancer at study entry (1992–1995). Baseline characteristics of participants of the Women’s Health Study have been described in detail (6). At the time of enrollment, participants gave written informed consent; completed questionnaires on demographics, medical history, medication, and lifestyle factors; and were asked to provide a blood sample. The study was approved by the institutional review board of the Brigham and Women’s Hospital (Boston, MA). The study complies with the Helsinki Declaration.

Participants were prospectively followed for a composite endpoint of 1st-ever major cardiovascular event (nonfatal myocardial infarction, nonfatal ischemic stroke, or cardiovascular death). Medical records were obtained for all women in whom a cardiovascular endpoint was reported to occur and were reviewed in a blinded fashion by an end-points committee of physicians. Myocardial infarction was confirmed if symptoms met WHO criteria and if the event was associated with abnormal concentrations of cardiac enzymes or diagnostic electrocardiograms. A confirmed stroke was defined as a new neurologic deficit of sudden onset that persisted for at least 24 h. Only ischemic strokes were included in this study. Death was confirmed to be from cardiovascular causes on the basis of an examination of autopsy reports, death certificates, medical records, and information obtained from the next of kin or other family members.

For each cardiovascular disease case, a control matched by age, smoking status, and length of follow-up was chosen among those who remained free of cardiovascular disease at the time the index event occurred in the case participant. The control participants were selected from those who remained event-free up to the date that the dataset was closed for selection of study participants. For the present investigation, 255 incident cardiovascular disease case-control pairs were identified. Of the 255 patients, 111 were diagnosed with myocardial infarction, another 111 were diagnosed with stroke, and 33 were confirmed to have died from cardiovascular causes. In this nested case-control analysis, the maximum length of follow-up was 5.9 years.

blood collection and laboratory evaluation
EDTA blood samples were obtained at the time of enrollment and stored in vapor-phase liquid nitrogen (–170 °C). For each of the cases and controls in this study, samples were thawed and analyzed in a core laboratory certified by the National Heart, Lung, and Blood Institute/Centers for Disease Control and Prevention Lipid Standardization Program.

We measured HSP27 plasma concentrations by use of ELISA (Calbiochem). This assay employs the quantitative sandwich enzyme immunoassay technique. Briefly, a monoclonal antibody specific for HSP27 was precoated onto a microtiter plate. Samples, standards, and controls were incubated along with a polyclonal HSP27 antibody in the microtiter plate. After incubation and a wash step, a horseradish peroxidase enzyme/IgG antibody conjugate was added. After another incubation and wash to remove unbound substances, an enzyme substrate was added and color was generated that was proportional to the amount of HSP27 present in the sample. Assays were run in duplicate and were repeated if the replicate CV was >10%. The interassay CVs of the assay at concentrations of 2.2 and 26.3 µg/L were 10.8 and 9.3%, respectively. The range of detection was 1–800 µg/L.

Total and HDL cholesterol were assayed directly with reagents from Genzyme and Roche Diagnostics with the use of a Hitachi 911 autoanalyzer. We measured C-reactive protein (CRP) with a high-sensitivity immunoturbidimetric assay on the Hitachi 917 autoanalyzer (Roche Diagnostics) with the use of reagents and calibrators from Denka Seiken; fibrinogen with an immunoturbidimetric assay, a mass-based assay with international standards (Kamiya Biomedical); and soluble intercellular adhesion molecule 1 (sICAM-1) with ELISA (R&D Systems).

statistical analysis
We first evaluated differences in baseline characteristics between case and control groups using paired t tests for gaussian-distributed, continuous variables, Wilcoxon signed-rank tests for continuous variables with skewed distributions, McNemar tests for dichotomous variables, and marginal homogeneity tests for variables with more than 2 categories. Paired tests were used because cases and controls were matched were matched on age, smoking, and length of follow-up, resulting in sample dependency (7).

Second, we examined associations between HSP27 plasma concentration and baseline characteristics of the control participants. Specifically, we calculated means, medians, and proportions of the baseline characteristics according to tertiles of HSP27 concentration at baseline. We used ln-transformed, continuous plasma concentration of HSP27 as the independent variable and tested for trends by using linear regression for continuous variables, logistic regression for dichotomous variables, and multinomial regression for variables with more than 2 categories. Furthermore, we computed Spearman correlation coefficients between HSP27 plasma concentration and baseline characteristics using both the cases and the controls.

To address the predictive value of baseline HSP27 concentrations, we calculated the relative risk of future cardiovascular events associated with HSP27 plasma concentration by logistic regression analysis, conditional on the matching on age, smoking (never, former, current), and length of follow-up. HSP27 plasma concentration was divided into tertiles based on the distribution in the controls, and the lowest tertile was used as the reference category. Analysis for trend was performed by entering ln-transformed HSP27 plasma concentration into the model as a continuous variable. Furthermore, we investigated the presence of a threshold effect by dichotomizing HSP27 plasma concentration based on the 50th, 75th, and 90th percentiles in the controls and entering it into the model. We used several levels of adjustment. Model 1 was matched on age, smoking, and length of follow-up. In model 2, we additionally adjusted for body mass index, systolic blood pressure, hypertension, total cholesterol, HDL cholesterol, hyperlipidemia, and diabetes. In model 3, we added CRP, exercise, alcohol intake, menopausal status, and hormone replacement therapy to the variables in model 2.

To examine effect modification, we stratified the above analysis on age (below and above the median), body mass index (<25, ≥25 to <30, ≥30 kg/m2), hypertension, hyperlipidemia, diabetes, smoking (never, former, current), CRP (≤3 and >3 mg/L), fibrinogen (below and above the median), and sICAM-1 (below and above the median). In these latter analyses, matching was broken to obtain enough power for the stratified analyses. Interaction terms were computed by entering the variables into the conditional logistic regression model as continuous variables (with values of 1, 2, and 3 for variables with 3 categories and values of 1, 2, 3, and 4 for variables with 4 categories).

All analyses were conducted with SPSS 13.0 for Windows (SPSS Inc.). A 2-tailed probability value of 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline characteristics of cases and controls are shown in Table 1 . As anticipated, cases had a significantly higher prevalence of established cardiovascular risk factors. Notably, CRP, fibrinogen, and sICAM-1 concentrations were also significantly higher in cases than in controls. The distribution of HSP27 plasma concentration was right-skewed, and median concentrations were similar in cases and controls (19.6 vs 18.6 µg/L, P = 0.58) (Table 1 ).


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  		Table 1. Baseline characteristics of cases and controls.

Table 2 displays baseline characteristics of controls according to tertiles of HSP27 plasma concentration. Age was inversely associated with HSP27 plasma concentration; mean age decreased from 63.4 in the lowest tertile of HSP27 to 58.0 in the highest tertile of HSP27 (P for trend <0.001). No significant trends were present in the remaining baseline characteristics. Spearman correlation coefficients are shown in Table 3 . HSP27 plasma concentration was significantly correlated with age (r = –0.258, P <0.001). Diabetes showed a borderline significant correlation (r = –0.087, P = 0.051). Correlation coefficients between the remaining characteristics and HSP27 plasma concentration were small and did not reach statistical significance. Adjustment for age did not materially change the estimates (data not shown), although it made the correlation with diabetes reach statistical significance (r = –0.098, P = 0.027).


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  		Table 2. Baseline characteristics according to tertiles of HSP27 plasma concentration among controls.


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  		Table 3. Correlation between HSP27 plasma concentration and baseline characteristics for all participants.

Odds ratios for cardiovascular disease are displayed in Table 4 . No trend was found when ln-transformed HSP27 plasma concentration was entered into the logistic regression model (odds ratio 1.00, 95% CI 0.83–1.21, P = 0.99). The odds ratio of developing cardiovascular disease for the highest vs the lowest tertile of HSP27 plasma concentration was 0.99 (95% CI 0.62–1.57). The risk estimates did not change materially when adjusted for other cardiovascular risk factors (Table 4 , models 2 and 3). We found no threshold effect when we dichotomized HSP27 plasma concentration based on the 50th, 75th, and 90th percentiles in the controls and entered it into the model (data not shown).


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  		Table 4. HSP27 plasma concentration and risk of cardiovascular disease.

When we entered interaction terms into the model, we found a possible interaction of HSP27 concentration and hyperlipidemia (P for interaction= 0.043). Stratification on hyperlipidemia resulted in a higher risk of cardiovascular disease associated with HSP27 concentration in hyperlipidemic individuals. However, the odds ratios did not reach statistical significance. No interactions were found with other characteristics, including lipid profile.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Contrary to our a priori hypothesis, in this prospective study, we found no association between baseline HSP27 plasma concentration and risk of future cardiovascular events among initially healthy women. Further, although HSP27 was inversely associated with age, it was not associated with other established cardiovascular risk factors.

HSPs represent the response of cells of the vessel wall to various stressors, including atherosclerosis risk factors (8). They fulfill chaperoning activity, and they appear to be important in preventing damage and in cellular repair processes after injury (9). HSPs have also been shown to regulate cell apoptosis (10). On the other hand, HSPs may also play a part in atherogenesis (1)(2). When cells are dying, intracellular HSPs are released into intercellular spaces to form soluble HSPs. HSP60 and 70 have been shown to bind to Toll-like receptor 4/CD14 complex, which is a soluble HSP receptor, resulting in expression of adhesion molecules by endothelial cells, proliferation of smooth muscle cells, and induction of several proinflammatory cytokines by macrophages. These inflammatory processes all contribute to the development of atherosclerosis (1). Furthermore, HSPs may serve as a link between infections and the atherosclerotic process. Infection with agents that contain homologous HSP proteins, such as Chlamydia pneumoniae, could induce an antiself response against HSPs expressed by endothelial cells of stressed arteries through molecular mimicry in susceptible individuals (2).

HSPs have been gaining interest in atherosclerosis research. HSPs from the HSP60 and HSP70 families and antibodies against these HSPs have been most widely investigated. Correlations have been reported between several of these factors and cardiovascular risk factors, such as LDL cholesterol and hypertension, and psychosocial measures, such as socioeconomic status and psychological stress (11)(12)(13). Furthermore, several of these factors have been associated with carotid disease and ischemic stroke (11)(14)(15), presence and severity of coronary atherosclerosis (16)(17), and restenosis after percutaneous transluminal coronary angioplasty (18). They have also been associated with aortic disease and peripheral vascular disease (19)(20)(21). More recently, increased concentrations of circulating HSP70 have been associated with low risk of coronary artery disease and with decreased intima-media thickness in hypertensive patients (22)(23).

However, little has been published on HSP27 in relation to atherosclerosis (3). With regard to the cardiovascular system, HSP27 has been reported to be differentially expressed in left ventricular samples from normal and failing dog myocardium (24). Mice overexpressing HSP27 were protected from lethal ischemia/reperfusion injury compared with their negative littermates (25). Increased expression of HSP27 protected against ischemic injury in adult rat cardiomyocytes (26). HSP27 was reported to act as an antiapoptotic protein against doxorubicin, a chemotherapeutic drug that may cause dilative cardiomyopathy and congestive heart failure (27). Also, expression of a specific diphosphorylated form of HSP27 was present in healthy blood vessels as opposed to vessels with cardiac allograft vasculopathy in patients who had undergone cardiac transplantation (28). Recently, it was reported that intracellular HSP27 allowed protection against plasmin-induced anoikis in human vascular smooth muscle cells and was inversely localized with apoptotic cells within culprit atherosclerotic carotid plaques (29). The role of HSP27 in the extracellular compartment remains unclear; exogenously added HSP27 was shown to prevent neutrophil apoptosis (30) but did not have any effect on plasmin-induced apoptosis in vascular smooth muscle cells (29).

To our knowledge, 2 clinical studies of HSP27 and atherosclerosis have been reported. We used atherosclerotic carotid and femoral endarterectomy samples and mammary and radial control endarteries to demonstrate that HSP27 secretion is decreased in atherosclerotic plaques compared with control arteries (4). Furthermore, secretion was barely detectable in complicated plaques. To confirm the hypothesis that plasma protein content can reflect arterial wall secretion, in the same study we measured soluble HSP27 concentration in the plasma of patients with carotid stenosis and healthy controls and showed that HSP27 plasma concentrations were decreased in atherosclerotic patients. In the 2nd study, Park et al. (5) compared HSP27 expression in carotid plaque core areas, normal-appearing areas from the same vessel specimens, and nonatherosclerotic renal and internal mammary reference arteries. Confirming the results obtained by us (4)(29), they reported that HSP27 expression is increased in the normal-appearing vessel adjacent to atherosclerotic plaque compared to both the plaque core area and the reference arteries (5). Contrary to the higher HSP27 expression, the phosphorylation of HSP27, which downregulates chaperone action and resistance against oxidative stress (3), was decreased in the normal-appearing areas. Furthermore, in the same study Park et al. reported that HSP27 plasma concentrations were increased in acute coronary syndrome patients compared with normal reference subjects. They also demonstrated that plasma concentration of HSP27 was significantly correlated with serum concentration of total cholesterol (r = 0.254, P <0.05), and was not correlated with age, sex, smoking, diabetes, and hypertension (5). It should be noted that Park et al. reported a mean HSP27 plasma concentration of 46 µg/L in their reference group; in our study this was 19 µg/L. Lack of assay standardization, differences in study population characteristics such as age, and modest sample size (Park et al. reference group, n = 29) may have contributed to this difference.

In contrast with the 2 above reports, no association was found between HSP27 plasma concentration and cardiovascular disease in the present study. To evaluate this discrepancy, strengths as well as limitations of our study should be considered. The present study is part of a large prospective cohort whose methods have been evaluated repeatedly (31)(32). In the nested case-control sample we used, cases had a higher prevalence of traditional risk factors such as hypertension and hyperlipidemia, as expected. Levels of blood biomarkers such as CRP and fibrinogen were also significantly higher in cases than in controls. To further confirm the robustness of the dataset, we ran conditional logistic regression analyses with the risk factors described in Table 1Up as the independent variables and cardiovascular events as the outcome. All factors significantly predicted events, in contrast to HSP27 (data not shown). Consequently, we expect that a true difference in HSP27 concentration between cases and controls, if present, would have been demonstrated. The quality of the HSP27 assay should also be addressed. The precision of the assay was monitored; the interassay CV ranged from 9.3% to 10.8%, and assays were run in duplicate and repeated if the replicate coefficient of variation was >10%. In view of these points, we consider it unlikely that the results of the present study are methodologically flawed.

Given this situation, the possibility that HSP27 plasma concentration might not closely reflect the secretion of HSP27 from atherosclerotic plaques should be considered as an alternative explanation for our results. If we address the hypothesis that HSP27 may be degraded by culprit atherosclerotic plaque (29), it is unlikely that variations in HSP27 plasma concentration could be detected until the disease is advanced, as demonstrated in patients with a mean age of nearly 70 years with carotid atherosclerosis (4). In this regard, we have recently observed increased plasma concentrations of proteolytic markers of neutrophil activation in these patients with carotid atherosclerosis (33).

Another possibility is that HSP27 plasma concentration rises in the acute phase of ischemic events, as shown for HSP70 (34), in which case raised plasma concentration would not precede cardiovascular disease. This would help to explain the results found by Park et al. (5), who studied acute coronary syndrome patients and drew blood within 24 h from presentation to the emergency department. The study design we used, with blood collection at baseline, does not allow demonstration of such an association.

Strengths of our study include the prospective study design, inclusion of 255 cases of cardiovascular disease, and the availability of detailed information on cardiovascular risk factors and several interrelated biomarkers, which made possible a profound analysis of the biomarker of interest. As such, apart from adjusting the analysis of the association between HSP27 plasma concentration and cardiovascular events for potential confounders, we were able to investigate whether HSP27 is associated with CRP and fibrinogen, inflammatory markers that may serve as measures for presence of infection, which itself could play a role in the induction of HSPs. We were also able to test the hypothesis that HSPs may result in expression of adhesion molecules by endothelial cells by investigating whether HSP27 is associated with sICAM-1.

Our study included female healthcare professionals who were mostly white and apparently healthy at study initiation. Therefore, the results may not be applicable to other populations such as those with advanced atherosclerosis or acute coronary syndrome, or men, especially since HSP27 has been shown to have an estrogen response element in its promoter (35)(36). Nonetheless, the present study does not support an association between baseline HSP27 plasma concentration and incident cardiovascular disease. Furthermore, it does not support associations between HSP27 plasma concentration and established cardiovascular risk factors, with the exception of an inverse correlation with age. Confirmation of these findings by other prospective studies is warranted.


   Acknowledgments
 
Grant/funding Support: This study was supported by the Leducq Foundation, Paris, France, with additional support from the Donald W. Reynolds Foundation, Las Vegas, Nevada, and the National Heart, Lung, and Blood Institute. I. Kardys is supported by grant 948-00-016 from the Research Institute for Diseases in the Elderly (RIDE) of the Netherlands Organization for Health Research and Development (ZonMw) and the foundation "Vereniging Trustfonds Erasmus Universiteit Rotterdam." The funding organizations had no role in the design of the study, the data collection, analysis and interpretation, the preparation of the manuscript, or the approval, delay, or disapproval of publication of the work.

Financial Disclosures: None declared.

Acknowledgments: We thank the participants of the Women’s Health Study for their conscientious cooperation and the entire Women’s Health Study staff for their expert assistance.


   Footnotes
 
1 Nonstandard abbreviations: HSP, heat shock protein; CRP, C-reactive protein; sICAM-1, soluble intercellular adhesion molecule 1.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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