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Ann Thorac Surg 2005;79:865-871
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Association of High Intracellular, But Not Serum, Heat Shock Protein 70 With Postoperative Atrial Fibrillation

^a Department of Cardiothoracic Surgery, St. George's Hospital and Medical School, London, United Kingdom
^b Department of Cardiological Sciences, St. George's Hospital and Medical School, London, United Kingdom

Accepted for publication August 5, 2004.

^* Address reprint requests to Dr Jahangiri, Department of Cardiothoracic Surgery, St. George’s Hospital & Medical School, London SW17 0QT, UK (E-mail: marjan.jahangiri{at}stgeorges.nhs.uk).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
BACKGROUND: Atrial fibrillation is a common arrhythmia, after cardiac surgery. Reperfusion injury and inflammation associated with cardiac surgery are thought to be involved in its pathogenesis. We hypothesized that cytoprotective effects associated with heat shock protein 70 (HSP70) could counteract these proarrhythmic insults. We therefore set out to examine the influence of heat shock protein 70 on the incidence of postoperative atrial fibrillation.

METHODS: We prospectively recruited 80 patients undergoing elective coronary artery bypass surgery. Blood samples were collected preoperatively. Right atrial tissue was obtained at surgery. Incidence of postoperative atrial fibrillation and its duration were noted. Using a nested case-control design, 15 patients who developed atrial fibrillation were matched for operative procedure, age, sex, and ß-blocker usage, with 15 controls from the remaining patients. Atrial heat shock protein 70 was subsequently quantified by immunohistochemistry. Serum heat shock protein was measured using enzyme-linked immunosorbent assay and high sensitivity C-reactive protein was determined by immunoturbidometric assay.

RESULTS: Intracellular HSP70 level was significantly higher in patients who did not develop atrial fibrillation (35 ± 13 vs 19 ± 15; p = 0.006). Atrial HSP70 level negatively correlated with atrial fibrillation; independent of other risk factors (odds ratio = 0.90; 95% confidence interval 0.84 to 0.99, p = 0.02). Serum HSP70 levels were similar in both groups (p = 0.81) and did not correlate with intracellular levels (p = 0.38). Preoperative C-reactive protein levels were similar in both groups (p = 0.93).

CONCLUSIONS: Intracellular, but not serum, HSP70 level is negatively correlated with postoperative atrial fibrillation. This suggests a cardioprotective and an antiarrhythmic role for intracellular HSP70.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Atrial fibrillation (AF) is a common arrhythmia following cardiac surgery [1, 2]. It is associated with significant morbidity and increased health care costs [3]. Postoperative AF is thought to be a likely consequence of inflammation and reperfusion injury associated with cardiac surgery, performed using either on-pump [4] or off-pump techniques [5].

Heat shock proteins (HSP) are a family of chaperone proteins which assist in preservation of cellular integrity by maintaining proteins in their correctly folded state, especially in stressful situations like those encountered during surgery [6, 7]. We have previously demonstrated that heat shock protein 70 (HSP70) has a cytoprotective function and limits necrosis of smooth muscle cells exposed to oxidative stress [8]. Increasing basal expression of HSP70 in myocardial cells also greatly enhances its resistance to ischemia-reperfusion injury [9, 10]. Higher myocardial levels of HSP70 are associated with reduced production of tumor necrosis factor- by the resident macrophages. The resultant decrease in inflammatory insult contributes to improved functional recovery following cardiopulmonary bypass (CPB) [11, 12]. C-reactive protein (CRP), a marker of systemic inflammation, has also been shown to be elevated in patients with paroxysmal AF, supporting the role of inflammation in AF [13].

Heat shock protein 70 is not only present within cells, but is also released into the blood to form soluble HSP70 [14]. Asea and colleagues [15] have previously shown that soluble HSP70 can bind to Toll-like receptor 4 and initiate signal transduction pathways, thereby inducing proinflammatory cytokines. These findings raise a possibility as to whether intracellular and soluble HSP70s have different roles. To clarify this issue and examine the influence of HSP70 on the incidence of postoperative AF, we assessed intracellular and soluble HSP70s in atrial tissue and blood of patients undergoing cardiac surgery.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
We prospectively recruited 80 patients, admitted to St George’s Hospital for elective coronary artery bypass surgery (CABG). One surgeon performed all of these operations. The following patients were excluded: (1) patients with history of chronic-paroxysmal AF; (2) patients with unstable angina, myocardial infarction, or infection within 6 weeks preceding surgery; (3) patients requiring redo surgery or other associated procedures, eg, valve surgery; (4) patients with inflammatory disorders like systemic lupus erythematosus; and (5) patients on immunosuppressive therapy. Demographic data, cardiovascular risk factors, and usage of medications, eg, ß-blockers were documented. St George’s Hospital Ethics Committee approved the study and informed consent was obtained from all patients.

Study Population
We used a nested case-control design. Out of the 80 patients, 15 patients developed postoperative AF and formed our "case-group." Another 15 patients, selected from the remainder, were matched for operative procedure, age ± 5 years, and sex and preoperative use of ß-blockers to form the "control-group." Atrial HSP70 and serum HSP70 content were measured only after the case-control groups were matched.

Perioperative Management
Preoperative medications, except aspirin and angiotensin-converting enzyme inhibitors were continued up to the morning of surgery. The same surgical and anesthetic protocols were applied. The CABG was performed using either on-pump or off-pump technique. Cold, blood based antegrade cardioplegia at a systemic hypothermia of 32°C was used in all cases requiring CPB. Off-pump surgery was performed at near normothermia (35°C). Operative data and postoperative complications were documented.

Postoperative AF
Postoperatively, heart rate and rhythm were continuously monitored by telemetry for the first 48 hours and by 4 hourly clinical examination thereafter. Patients underwent daily12 lead electrocardiograms (ECG) and had additional recordings if there was a clinical suspicion of arrhythmia. Postoperative AF, for the purposes of the study, was defined as the characteristic arrhythmia lasting for at least 15 minutes, occurring within the first week following surgery and requiring treatment for cardioversion. The arrhythmia had to be confirmed by a 12 lead ECG.

The ECG evaluation was performed independently by two observers. The discordances were resolved by common reevaluation. The date of onset and total duration of AF suffered was documented for each patient. All hemodynamically stable patients were started on ß-blocker (atenolol, 25 mg) on the first postoperative day. Patients in AF were treated with amiodarone, after correcting for electrolyte and acid-base imbalances.

Tissue Collection and Storage
Five mL of fasting blood sample was collected preoperatively. The sample was centrifuged and plasma was stored at –20°C for subsequent analysis. A block of tissue measuring 0.5 cm x 0.5 cm was obtained from the right atrial appendage immediately after opening the pericardium, before administration of heparin-initiation of CPB. This was snap frozen and stored in a liquid nitrogen tank until further use.

Immunohistochemical Analysis
Two 5 µm atrial cryosections from each of the patients were subjected to immunohistochemical staining for detecting HSP70. The antibody used was mouse monoclonal antihuman HSP70 (SPA-810, Stressgen, San Diego, CA), which recognizes an epitope in the region of amino acids 436 to 503 of inducible HSP70, with no reactivity with constitutive HSP70. Relevant negative and positive controls were used (Fig 1). A peroxidase-based detection system was used, with diaminobenzidin (DAB) as the final chromogen.

View larger version (127K): [in this window] [in a new window]   Fig 1. Representative panel of immunohistochemistry slides (40x) showing the difference in intraatrial heat shock protein 70 (HSP70) content in the two groups. (A) Negative control slide. (B) Slide from a patient who developed postoperative atrial fibrillation. (C) Slide from the corresponding control patient who did not develop postoperative AF. Arrow = HSP70 containing areas, stained brown with diaminobenzidin.

Three random high power fields from each slide were examined as detailed above and the average of these scores were used for the final analysis. The HSP70 quantification was performed without consulting the clinical detail of the patient to avoid bias.

Serum HSP70 Assays
Serum HSP70 (sHSP70) levels were determined using a commercially available enzyme-linked immunosorbent assay (StressGen Biotechnologies Corporation). The concentration of sHSP70 was determined by comparison with a standard curve, as per manufacturer’s instruction. The standard curve had a range of 0.78 to 50 ng/mL, and a sensitivity of 0.2 ng/mL. The assay was specific for inducible HSP70.

Western Blot Analysis
Proteins were extracted from frozen atrial tissue by grinding it into powder under liquid nitrogen and suspending it in lysis buffer (1 mL/10 mg of dry tissue). The supernatant was harvested and protein content measured. Proteins (30 µg/lane) were separated by electrophoresis through 8% sodium dodecyl sulfate (SDS) polyacrylamide gel under reducing conditions and transferred to an immobilon-p transfer membrane. The membranes were blocked with 5% nonfat dry milk and then probed with mouse monoclonal antihuman HSP70 antibody (SPA-810; StressGen). The resulting reaction was visualized using horseradish peroxidase-conjugated rabbit antimouse Ig secondary antibody (Dako), followed by incubation with 0.125 mL/cm² of the ECL Western Blot Detection Kit (Amersham Co, Little Chalfont, UK) for 1 minute. The blots were exposed to Hyperfilm (Kodak Ltd) for 5 minutes and immunoreactive bands developed for assessment. For analysis, HSP70 was normalized by dividing it by the corresponding value of actin; however, absolute values of HSP70 are shown in Figure 1.

High Sensitivity CRP
Fasting plasma CRP concentrations were analyzed by a latex enhanced, near infrared particle immunoturbidometric method using a Beckman synchron LX-20 pro autoanalyzer (Beckman Coulter, Buckinghamshire, UK). The sensitivity of this method was 0.2 mg/L. The intraassay coefficient of variation (CV) was 2.7% and interassay⁺ CV was 4.3%.

Statistical Analysis
Baseline characteristics were listed as mean ± standard deviation for continuous variables, n (%) for discrete variables. The differences between cases (postoperative AF) and the controls (no postoperative AF) were tested using the paired t test for continuous variables and the ² test for categorical variables. The CRP and sHSP70 were not normally distributed and were normalized by log_e transformation for analysis, although untransformed data are shown. Pearsons correlation was used to assess the association between atrial HSP70, sHSP70, and CRP and also for examining the relationship between atrial HSP70 and the duration of AF. Variables, significantly associated with postoperative AF in univariate analysis, were modeled into multifactorial logistic regression equation to assess their interactions. A pvalue less than or equal to 0.05 (2-tailed) was considered statistically significant. All analyses were done using StatView (version 5.01; SAS Institute Inc, Cary, NC) statistical software.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
Comparison of Cases and Controls
Characteristics of cases and controls are summarized in Table 1. There was no statistically significant difference in the prevalence of various cardiovascular risk factors in the two groups. The duration of CPB, cross-clamp time, and extent of systemic hypothermia were similar. There were no significant differences in postoperative infection, transfusion requirement, and renal dysfunction.

Multivariate analysis confirmed significant association between atrial HSP70 and postoperative AF. This was independent of age, sex, duration of ventilation, duration of inotropic support, and intensive therapy unit stay (odds ratio [OR] = 0.90; 95% confidence interval [CI] 0.84 to 0.99, p = 0.02). The rest of the variables lost statistical significance (p > 0.32). All patients with postoperative AF regained sinus rhythm with treatment. The median duration of AF suffered was 10 hours (5 to 15 hours). Twelve (80%) patients developed AF within 48 hours after surgery. There was a negative correlation between atrial HSP70 level and duration of AF though this did not reach statistical significance (r = -0.30, p = 0.27).

Atrial HSP70 and Occurrence of Postoperative AF
The atrial specimens were stained with a monoclonal antibody against inducible HSP70. The HSP70 immunostaining was present in almost all of the atrial sections but the pattern-extent was different between the two groups. The pattern of HSP70 staining in the atrial tissues is shown in Figure 1. Nonspecific reactivity was minimal, as was evident in the negative controls (Fig 1A). The atrial myocardium from patients with postoperative AF mostly showed areas with weak staining (Fig 1B), whereas HSP70 staining in atria of patients without AF displayed elevated HSP70 content in the cardiomyocytes (Fig 1C). Heterogeneity of HSP70 staining was more evident in some case-control pairs and less in others. The HSP70 staining in tissues appeared to be related more to the cellular than extracellular components, as demonstrated on immunostained sections by counterstaining with Mayer's hemalaum.

Atrial HSP70 content was significantly higher in patients who did not develop postoperative AF (35 ± 13 vs 19 ± 15; p = 0.006). These results held true even in subgroup analyses of on-pump (38 ± 13 vs 21 ± 16, p = 0.01; n = 22) and off-pump surgery (28 ± 14 vs 14 ± 11, p = 0.18; n = 8). To confirm the immunohistochemical results, we performed western blot analysis of atrial protein extracts from both these groups. The quantification of HSP70 proteins in western blot analysis showed significantly higher protein level in subjects without postoperative AF (1,477 ± 547 vs 773 ± 173, p = 0.007; Fig 2).

View larger version (40K): [in this window] [in a new window]   Fig 2. Difference in heat shock protein 70 (HSP70) band area-intensity, as shown by western blot analysis of atrial protein extracts. A representative western blot (inset) from the same case-control pair whose immunohistochemistry slides are shown in Figure 1. (AF = atrial fibrillation; OD = outer diameter.) +p = 0.007.

View larger version (17K): [in this window] [in a new window]   Fig 3. The relationship between atrial and serum soluble heat shock protein 70 (HSP70) levels. (A) Patients (n = 15) who developed postoperative atrial fibrillation. (B) Patients (n = 15) who did not develop postoperative atrial fibrillation.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

Postoperative AF is a probable consequence of the electrophysiological disturbances, associated with reperfusion injury and inflammation, seen in cardiac surgery patients. Reperfusion injury related arrhythmias have been demonstrated in both on-pump [4] as well as off-pump [5] surgery patients. Increased HSP70 expression has been shown to attenuate CPB induced inflammation [18], preserve cellular integrity by limiting mitochondria-related apoptosis [19], and reduce reperfusion arrhythmias [20, 21]. High cytosolic HSP70 allows maturation of cardiac potassium channel hERG [22], even in the face of ischemia. Preservation of such critical ion channels could be a possible explanation for the better electrophysiologic recovery and decreased arrhythmias associated with higher HSP70 levels.

The significantly higher atrial HSP70 levels observed in patients without postoperative AF, compared to those with AF, implies a protective function for HSP70 (OR = 0.90, p = 0.02). Furthermore a negative correlation, though not statistically significant, between atrial HSP70 levels and the duration of AF, is compatible with the same trend and supports the previous conclusion. These inferences are in line with the published studies and suggest a cytoprotective and antiarrhythmic role for atrial intracellular HSP70.

Three issues in the methodology deserve further expansion. First, when choosing the "controls" we matched them for the operative procedure; age ± 5 years, sex, and ß-blocker usage. Matching for the operative procedure not only adjusted for the pathology but also the surgery-related ischemia-reperfusion stress, both of which would influence the expression of inducible HSP70 [11] and predisposition for developing postoperative AF. Similarly, the subjects were matched for age [23], sex [24], and ß-blocker usage because they are known to influence the occurrence of postoperative AF. Second, we chose antiHSP70 mouse monoclonal antibody, which detects only the inducible HSP70 (HSP72) in the atrial tissue and not its constitutive part (HSP73). This choice was prompted by the reports [11, 20] which showed that only inducible HSP70 levels correlated with the degree of myocardial preservation and antiarrhythmic effect, following ischemia-reperfusion injury. In our study, atrial biopsy was obtained immediately after opening the pericardium, before administration of heparin-initiation of CPB. Inducible HSP70 level in such relatively unstressed atrial myocytes reflects basal expression of HSP70 and possibly represents a more efficient stress handling mechanism at the disposal of these cells. The reasons for observed differences in baseline expression of HSP70 are not known, however we think genetic factors may be involved. Third, we included patients undergoing both on-pump as well as off-pump cardiac surgery in our study. The suggested role of on-pump surgery-related inflammation in the causation of postoperative AF [4] has been questioned in various studies [25, 26]. Furthermore, the study of Ascione and colleagues [4] showing a higher incidence of AF in the on-pump group did not administer prophylactic ß-blocker after surgery, which was in contrast to our study.

The use of computer-aided analysis of the stained slides [16] allowed for reproducible measurements of atrial HSP70 level. The difference in HSP70 expression, between the two groups, was also confirmed by western blot analysis. This methodological approach was more robust and in contrast to that of St Rammos and colleagues [2]. Furthermore, their study had included patients undergoing both coronary artery bypass and/or valve surgery. The pathophysiology of postoperative AF in each of these clinical settings is different.

An important observation in this study was the lack of significant correlation between the atrial intracellular HSP70 and serum soluble HSP70, and that there was no association between serum soluble HSP70 and occurrence of postoperative AF. These findings have several implications. First, HSP70 may have protective abilities only when it localizes intracellularly [11] and loses its protective role when it is released into blood. Second, soluble HSP70 concentrations may be a marker of cell injury induced by severe stress and are not reflective of intracellular levels. Finally, soluble HSP70 might function as a cytokine-like protein as suggested by other studies [15]. To verify this hypothesis, further studies would be needed.

There was no difference in the preoperative CRP levels between the two groups in our matched study population and is consistent with the results of Bruins and colleagues [27]. This could also be due to the small sample size. Chung and colleagues [13] have demonstrated the association between baseline CRP and AF, only in patients with persistent-chronic AF and not in cases with a single episode of short-term AF after surgery.

The results of our study must be viewed in the light of its limitations. We used continuous telemetry only in the first 48 hours. This could have resulted in missing some of the transient asymptomatic AF. However, such episodes should have occurred in both the groups and are unlikely to affect our results. Furthermore, this is an association study and underlying mechanisms remain to be clarified. Though the literature supports the antiarrhythmic role of intracellular HSP70, the association shown could be an epiphenomenona. Antiarrhythmic effects associated with HSP70 expression [20] may be just a marker for better stress handling capacity of an individual. Larger studies are needed to address all these issues.

In summary, higher atrial HSP70 level, but not serum HSP70, is associated with reduced incidence of AF after coronary artery bypass surgery. This observation suggests an antiarrhythmic and a protective function for intramyocardial HSP70. Myocardial preconditioning, by preoperative induction of HSP70, could be a useful strategy for decreasing the incidence of postoperative atrial fibrillation and it’s associated complications.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Kaushik Mandal Marjan Jahangiri Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mandal, K. Articles by Jahangiri, M. Search for Related Content PubMed PubMed Citation Articles by Mandal, K. Articles by Jahangiri, M. Related Collections Electrophysiology - arrhythmias Related Article