Ann Thorac Surg 2004;78:883-889
© 2004 The Society of Thoracic Surgeons
Original article: cardiovascular
Detection of anti-hsp70 immunoglobulin G antibodies indicates better outcome in coronary artery bypass grafting patients suffering from severe preoperative angina
Sebastian Vogt, MDa,*,
Irene Portig, MDb,
Björn Kusch, MDa,
Sabine Pankuweit, MDb,
Abdul Sami Sirat, MDa,
Dirk Troitzsch, MDa,
Bernhard Maisch, MDb,
Rainer Moosdorf, MDa
a Department of Cardiovascular Surgery, Marburg, Germany
b Department of Cardiology, Philipps-University Hospital, Marburg, Germany
Accepted for publication March 30, 2004.
* Address reprint requests to Prof Dr Vogt, Klinikum der Philipps-Universität Marburg, Herzzentrum, Klinik für Herz-und thorakale Gefässchirurgie, Baldingerstrasse, D-35043 Marburg, Germany
vogts{at}med.uni-marburg.de
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Abstract
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BACKGROUND: Recent findings indicate that molecular chaperones actively participate in myocardial cytoprotection. Moreover, ischemic tolerance can be induced in humans by brief ischemic events. Therefore, we investigated patients with severe angina attacks before coronary artery bypass grafting. We focused on appearance of anti-hsp70 antibodies as an immunologic response to heat shock protein induction by ischemia followed up by hemodynamic measurements perioperatively. We correlated these clinical findings with the presence of antibodies against hsp70 and the antioxidative capacity of patients' sera.
METHODS: Thirty-five consecutive patients with coronary artery disease scheduled for coronary artery bypass grafting were included. Seventeen patients had severe angina, and 18 patients suffered from chronic stable angina preoperatively. In the patients' sera, antibodies against hsp70 were detected by enzyme-linked immunosorbent assay, and antioxidative capacity was detected using the chromogen assay. Cardiac output and pulmonary capillary wedge pressure were measured using a thermodilution catheter. We also evaluated C-reactive protein and creatine kinase MB isoenzyme, and performed a conventional leukocyte count.
RESULTS: The sera of the 17 patients with severe angina attacks before surgery contained antibodies against hsp70 and a low antioxidative capacity. The interval between a severe angina attack and anti-hsp70 antibody titer are inversely correlated. These patients had better cardiac output and lower pulmonary capillary wedge pressure values after surgery.
CONCLUSIONS: Severe angina before cardiac surgery coincided with an improved outcome as measured by hemodynamic variables as compared with chronic stable angina. This finding correlated significantly with a low antioxidative capacity and the presence of antibodies against hsp70. These pathophysiologic mechanisms might therefore play a role in myocardial protection.
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Introduction
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After brief ischemic events, protection of the myocardium against future ischemic events can be induced [1]. Two distinct forms have been reported, the short-lived, classic form, which subsides within 2 hours, and a second form appearing 24 hours after the preconditioning ischemic event, referred to as a second window of preconditioning. Concerning inducibility and pathogenetic mechanism, both forms show marked differences among species. However, the adenosine triphosphate–sensitive potassium channel plays an important role in both forms, as well as expression of stress proteins (hsp), their interaction with the endothelial nitric oxide synthetase, and their influence on transcription factors for nuclear factor kappa B and activation protein 1 on the one hand, and superoxide dismutases on the other [2]. It appears that the expression of hsps provides a conditioning effect to the myocardial energy metabolism in terms of reducing the energy turnover, thus reducing the effect of injury to the myocardium with ischemic events. Moreover, hsps seem to participate in the protection against myocardial dysfunction probably as a result of enhancement of mitochondrial energy turnover [3].
In patients who had experienced of angina 24 hours before an ischemic event, Kloner and Yellon [4] and Kloner and colleagues [5] reported in the TIMI-9B study a lower incidence of death, reinfarction, and heart failure or shock. These effects were dependent on the patients' age and on the interval between preinfarct angina and the actual myocardial infarction: if the interval exceeded 24 hours, the protective effect was no longer present [4, 5].
Inasmuch as we have recently been able to show that the expression of hsps is correlated with improved hemodynamic variables after induced cardioplegic arrest in rabbits [6], we investigated in this study from a cardiosurgical standpoint whether severe presurgical angina improves hemodynamic variables and clinical outcome of patients after coronary artery bypass grafting (CABG). Postoperative hemodynamic variables were then correlated with the antioxidative capacity (AOC) of the patients' blood, a variable known to reflect the liberation of free radicals during myocardial ischemia, and with the presence of antibodies against stress proteins, and specifically hsp70, known to be induced in patients with symptomatic coronary artery disease, probably as a consequence of stress protein induction or cell injury [7].
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Material and methods
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Patients were included in this study after we obtained their written consent. The study was approved by the local ethics committee.
Patients
The study group included 35 patients referred for elective CABG surgery. The patients included 17 cases of severe unstable angina and 18 cases of chronic stable angina before the revascularization procedure. All the patients with primary unstable angina (class B) had an absence of electrocardiographic or cardiac enzyme changes as a sign of myocardial infarction, when crescendo angina occurred. They suffered from angina pectoris at rest as well as with minimal exertion (class II). The episodes of angina pectoris occurred in the presence of standard therapy for chronic stable angina. The preoperative drug regiment was then converted to heparinization and nitroglycerin, intravenously (heparin 10 IU/kg body weight per hour; nitroglycerin 0.5 to 1.0 µg · kg–1 · min–1).
Exclusion criteria comprised the existence of peripheral arterial occlusive disease and significant carotid stenoses. Patients with previous cardiac surgery, known myocardial infarction, capillary obstructive pulmonary disease, and acute abdominal affections (eg, pancreatitis) were excluded from the study group. All patients underwent a routine procedure with median sternotomy and use of cardiopulmonary bypass.
Measurement of hemodynamic variables and blood sampling
Each patient received (according to standard preoperative care protocol) preoperatively a 7F thermodilution catheter (Baxter-Edwards, Irvine, CA) by means of the internal jugular vein or right subclavian vein to measure cardiac output and pulmonary capillary wedge pressure. Measurements were taken before surgery in the operating room and postoperatively before the patient's transfer to the intensive care unit. Evaluation was performed using a Baxter-Edwards Central Care Explorer. Blood was drawn from this central venous catheter before and 0.5, 6, and 24 hours after surgery. Sera were stored at –20°C until use.
Detection of anti-hsp70 antibodies
Detection of anti-hsp70 antibodies was performed using an enzyme-linked immunosorbent assay in a double-blind study protocol. The control group of negative sera for the assay consisted of 35 age-matched and sex-matched individuals with no previous history of cardiac or vessel disease. Results were not disclosed until the end of the investigation.
Enzyme-linked immunosorbent assay
Purified hsp70 (Stressgen, Victoria, British Columbia, Canada) was diluted in 0.1 mol/L bicarbonate buffer, pH 9.5, to a concentration of 0.25 µg/mL, and 100 µL was dispensed into each well of a microtiter plate (Maxisorb; Nunc, Roskilde, Denmark). After incubation overnight at 4°C, plates were washed three times with Tris-buffer (0.01 mol/L Tris chloride, 0.15 mol/L saline), and 150 µL of blocking buffer (5% weight/volume sucrose and 5% volume/volume Tween in Tris buffer) was added for 1 hour to inhibit nonspecific binding. Sera were diluted 1/200 in blocking buffer, and the peroxidase-conjugated anti-human immunoglobulin (Ig) G or IgM antibody (Jackson ImmunoResearch, West Grove, PA) was diluted 1/10,000 in washing buffer (0.5% Tween-20 in Tris buffer). One hundred microliters of diluted serum or antibody was added per well and incubated at room temperature for 2 hours or 1 hour, respectively. Between each step, plates were washed with washing buffer three times for 2 minutes. One hundred microliters of K Blue substrate (Neogen, Lexington, KY) was placed in each well and left at room temperature for 30 minutes. The enzyme reaction was stopped by adding 25 µL of 2 mol/L sulfuric acid. The absorbance at 450 nm was read in a Labsystems Multiscan enzyme-linked immunosorbent assay reader (Labsystems OY, Helsinki, Finland). Each serum was tested in duplicate both in antigen-coated and noncoated wells. A positive and a negative reference serum was included on each plate. To reduce unspecific binding, various blocking protocols and microtiter plates were evaluated, leading to the protocol described above. A serum sample was considered positive for antibodies against hsp70 if the optical density exceeded a prospectively defined cutoff value. The cutoff value was determined using age-matched and sex-matched control sera from healthy individuals without a history of coronary heart or peripheral artery disease. The mean of the optical density values obtained plus 2 standard deviations was 0.06. Because optical density values of the antibody-positive sera were low, further dilutions to determine antibody titers were not performed. To determine specificity, sera were preincubated with 10 µg/mL hsp70 or 10 µg/mL hsp60. Because antibody titers were low, IgG was not purified for additional control purposes.
Antioxidative capacity
Testing of AOC was performed using a commercially available kit from Randox Laboratories Ltd (UK). The test uses the chromogen ABTS (2,2'-acino-di-3-ethylbenzthiazolinesulfonic acid) for proof of the antioxidant status of the serum sample. For generating the radical ABTS, the chromogen is incubated together with a peroxidase (met-myoglobin) and hydrogen peroxide. The blue-green color of the chromogen is detected by spectrophotometer at 600 nm. The AOC of each individual probe causes color differences proportional to the concentration of antioxidants in the sera. Measurements were performed with a spectrophotometer from Perkin-Elmer 
5 UV/Vis at 37°C. Results were given in millimoles per liter.
Detection of creatine kinase
Evaluation of creatine kinase (CK) enzyme activity was performed using a commercially available ultraviolet spectroscopic test (Roche Diagnostics GmbH, Mannheim, Germany). Quantitative evaluation of the corresponding isoenzyme CK-MB was performed using a immunologic ultraviolet test of the same company. All blood samples were analyzed in a Roche/Hitachi 917 automatic analyzer. Samples were taken preoperatively in the operating room and 12 hours after surgery and analyzed immediately.
Inflammatory variables
A conventional leukocyte count and testing of elevated C-reactive protein by nephelometric analysis was performed.
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Results
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This study comprises 35 patients with angiographically proven coronary artery disease. Patients were divided into two groups on the basis of the classification of angina pectoris. In group one, patients had had severe angina attacks 8 to 35 days before surgery, developing when resting, and were negative for troponin-I in each case, necessitating hospital referral. In group two, patients had stable chronic angina developing on exercise only and no severe attacks within the last 3 months. Corresponding clinical variables are listed in Table 1. No significant differences were noted in patient characteristics between both groups preoperatively.
Detection of antibodies against hsp70
In group two (chronic stable angina, n = 18 [51%]), the majority had no antibodies against hsp70; in group one (severe angina, n = 17 [49%]), the majority had serum IgG antibodies against hsp70. The titers were low as compared with positive control samples (patients with systemic lupus erythematosus; Fig 1); IgM antibodies could not be detected. False-positive results caused by unspecific binding could be excluded by control tests with secondary antibodies run simultaneously. Specificity was confirmed by almost complete inhibition when anti-hsp70 antibodies were removed from sera when hsp70 was added to the test, whereas addition of hsp60 did not alter results. Optical density values did not alter significantly in sera drawn immediately prior and 0.5, 6, and 24 hours after surgery (data not shown). Antibody titer roughly correlated with the interval between the latest severe angina attack and CABG (Fig 2).
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Fig 1. Prevalence of anti-hsp70 antibodies as measured by enzyme-linked immunosorbent assay in sera of patients before surgical coronary artery bypass grafting. Of 35 patients referred for coronary artery bypass grafting, 17 had unstable angina and 18 had stable angina. The control group consisted of 35 age-matched and sex-matched individuals without previous history of cardiovascular diseases. These sera were used to determine the cutoff prospectively (mean of optical density values plus 2 standard deviations).
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Fig 2. Correlation between anti-hsp70 antibody titer and interval between severe angina attack and coronary artery bypass grafting (CABG). Correlation analysis was performed with SPSS for Windows 2000 (SPSS GmbH, Munich, Germany).
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Hemodynamic variables
All 35 patients showed a clear increase in postoperative cardiac output (3.35 ± 0.78 L/min versus 6.68 ± 1.56 L/min, p < 0.001 and 3.37 ± 0.78 L/min versus 5.39 ± 1.49 L/min, p < 0.001). However, postoperative values were higher in patients whose serum contained antibodies against hsp70 as compared with the anti-hsp70–negative group (6.68 ± 1.56 L/min versus 5.39 ± 1.49 L/min; p < 0.01). Pulmonary capillary wedge pressures were slightly lower in both groups (14.67 ± 2.62 mm Hg versus 11.17 ± 3.48 mm Hg; p = 0.014; Fig 3).
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Fig 3. Cardiac output and pulmonary capillary wedge pressure in patients whose serum did or did not contain anti-hsp70 antibodies. Both groups showed a postoperative increase in cardiac output, with a greater increase in anti-hsp70–positive patients. The latter also had a greater decrease in pulmonary capillary wedge pressure (Student's t test). Black bars = severe angina; grey bars = chronic stable angina. (CABG = coronary artery bypass grafting.)
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Evaluation of antioxidative capacity
Immediately after surgery, a decrease of the AOC was seen in both groups. Direct comparison revealed a higher reduction of AOC in patients whose serum contained antibodies against hsp70 as compared with the anti-hsp70–negative group (p = 0.0007) (Fig 5).
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Fig 5. Time course of antioxidative capacity in both groups. Shortly after surgery antioxidative capacity decreases, showing significantly lower levels in the anti-hsp70 antigen–positive group (p = 0.0007, Student's t test). (CABG = coronary artery bypass grafting.)
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Evaluation of creatine kinase-MB
Figure 4 shows the postoperative trends of the myocardial isoenzyme of CK in both groups with no significant difference between the groups.
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Fig 4. Postoperative activity of the creatine kinase MB isoenzyme. Values are shown as median. Concentrations in both groups decrease. Individuals with positive hsp70 antibody have slightly higher creatine kinase MB values. Differences between both groups are not significant (Student's t test). (CABG = coronary artery bypass grafting.)
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Evaluation of inflammatory markers
Testing of C-reactive protein showed large variations in values as often seen after surgical trauma and extracorporal circulation and therefore allowed no statistical interpretation (Table 2). Leukocyte counts showed an increase from 7.33 ± 1.59 versus 13.33 ± 4.86 x 106 cells/mL (severe angina) to 7.46 ± 1.69 versus 13.82 ± 11.06 x 106 cells/mL (chronic stable angina) at 24 hours after surgery with no significant difference within both groups.
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Comment
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In 1988, Fedele and colleagues [8] showed that a reduction of coronary blood flow distal to a severe coronary artery stenosis and after an acute myocardial infarction can be tolerated by myocardial tissue. Apparently, the myocardial oxygen need is reduced to the amount of oxygen offered. Thereby a stability of metabolic turnover on a low level seems to be established, and the vitality of the tissue is guaranteed up to a certain degree [8]. On the basis of these studies, other groups found contractile dysfunction without reduced coronary blood flow after brief ischemic events. In the case of hibernating myocardium, studies have shown a primary downregulation of local myocardial oxygen consumption distal to the critical coronary artery stenosis [9], a state that appears to be equivalent to unstable or chronic stable angina: symptoms observed in our patients before CABG. However, hibernating myocardium is usually accompanied by a reduction in contractility in myocardial tissue distal to the critical stenosis, which was not observed in our patients by preoperative angiography. This paper addresses additional mechanisms that are suggested to protect the myocardium when a severe angina occurs in patients with a known chronic ischemic disease.
Various studies reported a protective effect of stress proteins on myocardium. The most convincing results as to the protective effect of hsp70 come from transfection studies and transgenic mouse models [19]. Other studies were able to show that a reduction in infarct size as well as improved contractile function could be correlated with the induction of stress proteins and occurred after periods of brief ischemia instigated 24 hours before sustained ischemia [10, 11]. The extent of this protective effect is dependent on the interval between stress and the subsequent ischemia, as well as on the quality of stress applied. Thermal preconditioning, for example, induces hsp70 expression to a higher extent than do metabolic stress factors [12]. These stress proteins appear within 3 hours after thermal stress, are seen for additional 72 hours, and decrease thereafter. After 168 hours hsp70 is undetectable [13].
Conformation of precursors of mitochondrial proteins is secured by cytosolic chaperones. Depending on their conformation, proteins bind to extramitochondrial receptors and are transferred into the mitochondrion, an adenosine triphosphate–dependent process. For example, apocytochrome c is directly transported through the extramitochondrial membrane, but is still covalently bound to heme by cytochrome c–heme lyase, resulting in the implantation of cytochrome c on the inner membrane of the mitochondrial compartment. Intramitochondrial hsp70 chaperones enable translocation of precursor proteins into the matrix. Import of proteins is obviously dependent on the mitochondrial membrane potential. When sequences of precursor proteins of the introduced protein are removed, interaction with hsp60 induces final conformation and transport to the inner membrane [14–16]. During ongoing ischemia an induction of the enzymes of the respiratory chain and the corresponding chaperones is suggested. In contrast to chronic stable angina, severe angina could trigger exposure of hsp70 antigen to immunocompetent cells, resulting in detectable antibody production. Thus, hsp70 induction could be protective in CABG surgery and is reflected by anti-hsp70 antibody production in patients with severe angina preoperatively. Interestingly, antibodies detected were from the IgG class, as seen in natural antibodies or in repeated as opposed to a fresh exposure to a new antigen.
Tumor necrosis factor 
production of macrophages or of the myocardium during ischemia is suppressed by the induction of hsps and is effective in cardioprotection against postischemic dysfunction [17]. Here as well, anti-hsp70 antibodies might be induced by exposure of hsp70 subsequent to an acute ischemic stimulus.
According to our current knowledge of their function, stress proteins merely play a small part in a larger network that reacts in response to different types of stress [18, 19]. The accumulation of hsp70 in the nucleus has a negative effect on the activity of poly(adenosine diphosphate–ribose) synthetase and reduces an excessive consumption of phosphate during reoxygenation [20, 21], which is one of the cellular mechanisms to save energy and to keep the integrity of the cell during ischemia. Furthermore, hsp70 interacts with contractile proteins by downregulation of messenger RNA for phospholamban and the calcium adenosine triphosphatase of the sarcoplasmatic reticulum shown in hibernating myocardium. At this point it is important to note that ischemic tolerance is not caused exclusively by stress protein expression by itself; posttranslational mechanisms and the translocation of stress proteins contribute to some extent. Meldrum and associates [22], for example, report a suppression of myocardial contractile dysfunction by stress protein conditioned inhibition of nuclear factor kappa B translocation, as well as stress protein binding to cytosolic tumor necrosis factor. Some of these downstream mechanisms may outlast the interval in which the induction of stress proteins can directly be detected by an increase in hsp70 messenger RNA and hsp70 protein, and may lead to a more durable effect as seen in our study population, which may correlate with the presence of (possibly regulatory) antibodies against hsp70.
In acute coronary syndrome, a heat shock paradox has been observed, a phenomenon probably linked to the activity of nuclear factor kappa B and its counterpart inhibitory kappa B [23]. Cells primed by heat stress can be protected against inflammatory reactions, whereas cells primed by an inflammatory reaction may die during a subsequent thermal stress. Because CABG with the use of cardiopulmonary bypass triggers an inflammatory reaction, the induction of hsp70 in myocardial tissue in itself may not reflect a cardioprotective effect. But the release of hsp70 into the circulation leading to a modulation of CD14 and toll-like receptor 4 expression, and thereby innate immunity [24], may be partly abolished by the presence of antibodies against hsp70. This regulatory effect may prevent the initiation of an excessive inflammatory response with all its negative implications on circulatory properties. In this context it is of interest that a positive correlation could be established between the anti-hsp70 antibody titer and the interval between a severe angina attack and CABG. It is tempting to speculate that anti-hsp70 antibodies and antiidiotypic antibodies are among the regulatory processes involved, which might be able to explain why antibody titers were low. Proof of the existence of such a regulatory function will be difficult to obtain in a clinical setting.
Heat shock protein 70 released into the circulation may interfere with the detection of anti-hsp70 antibodies in our enzyme-linked immunosorbent assay. Because antibody responses were determined immediately before CABG and antibody titer did not change significantly 0.5, 6, and 24 hours after surgery (covering the time frame in which release of hsp70 has previously been reported), a major influence is not likely. Inasmuch as antibody titers were low, purification of the IgG fraction to exclude interference of other serum proteins with the test system used here was not feasible.
During ischemia, free oxygen radicals appear to be harmful agents, inducing apoptosis in myocytes [25]. Reactive oxygen radicals contribute to the pathophysiology of vascular diseases such as coronary artery disease. On the one hand, an increase in reactive oxygen species during ischemia-reperfusion with consecutive adverse effects exerted by oxygen radicals on myocardium has been established, although controversy still exists regarding the beneficial effect of the oral administration of antioxidants. On the other hand, free radicals and peroxynitrite have been shown to be triggers of late preconditioning in animal models, and this preconditioning effect could be prevented by scavengers of free radicals. The results of our study seem to confirm the latter findings, in that a negative correlation was found between the extent of the AOC in plasma and postsurgical outcome as measured by hemodynamic variables (see Fig 3 and Fig 5).
Considerable controversy exists regarding reproducibility and even existence of late preconditioning in various species, including human. In humans published data stem from studies including patients undergoing percutaneous transluminal coronary angioplasty and CABG, in which the stimulus for induction of ischemic preconditioning was usually administered immediately before intervention, ie, early preconditioning on the one hand, and patients with myocardial infarction and preinfarct angina on the other. In the TIMI-9 study, onset of angina within 24 hours of myocardial infarction was associated with a lower 30-day cardiac-related event rate and a trend toward lower peak CK compared with angina before 24 hours. This finding is in contrast with other studies, in which any preinfarction angina was associated with lower CK values and better outcome [4, 5].
Therefore, from these studies neither the time frame in which ischemic tolerance occurs be inferred nor its mechanisms understood. The data presented here suggest that, at least in humans, the second window of preconditioning is either much wider than previously anticipated or that additional mechanisms are at work.
In conclusion, our study indirectly confirms that ischemic tolerance can be induced by severe angina attacks in humans. Whether the underlying mechanisms are equivalent to late ischemic preconditioning as seen in animal models with a wider time frame or are the result of a third protective mechanism remains to be elucidated. In our study population, ischemic tolerance was accompanied by a lower AOC and the presence of anti-hsp70 antibodies: both candidates are known to be involved in the pathophysiologic events.
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Related Article
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Invited commentary
- Daniel R. Meldrum
Ann. Thorac. Surg. 2004 78: 889.
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Abstract
Introduction
