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Eur J Cardiothorac Surg 2007;32:639-643. doi:10.1016/j.ejcts.2007.06.041
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

Inducible NO synthase expression in endomyocardial biopsies after heart transplantation in relation to the postoperative course

Achim Kocha,1,*, Andreas Burgschweigerc,1,**, Esther Herpelb, Falk-Udo Sacka, Peter Schirmacherb, Gabor B. Szaboa, Matthias Karcka, Philipp A. Schnabelb

a Department of Cardiac Surgery, University of Heidelberg, Germany
b Institute of Pathology, University of Heidelberg, Germany
c Department of Cardiology, Theresien-Hospital, Mannheim, Germany

Received 22 March 2007; received in revised form 21 June 2007; accepted 27 June 2007.

* Corresponding author. Address: Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Tel.: +49 6221 5636191; fax: +49 6221 565585. (Email: achim_koch{at}med.uni-heidelberg.de).
** Corresponding author. Address: Department of Cardiology, Theresien-Hospital, Bassermannstr. 1, D-68167 Mannheim, Germany. (Email: achim_koch{at}med.uni-heidelberg.de).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Objective: Ischemia and reperfusion during heart transplantation cause damage to cardiomyocytes and endothelial cells and may initiate later acute rejection. Free oxygen radicals generated by iNOS are widely accepted to be responsible for ischemic injury. Increased iNOS expression on cardiac tissue may represent a more intensive tissue injury during ischemia and reperfusion in heart transplantation. The aim of this study was, therefore, to test the hypothesis that increased iNOS expression in early postoperative endomyocardial biopsies correlates with rejection or infection episodes in the later postoperative course. Patients and methods: Right ventricular endomyocardial biopsies were obtained from heart transplantation recipients at transplantation and during the first 2 weeks postoperatively. The recipients were divided into three groups depending on the postoperative course during the first year after transplantation: patients in group 1 had an uncomplicated postoperative course, patients in group 2 developed significant signs of postoperative infection, while patients in group 3 presented with acute rejection (≤grade 2R ISHLT). The expression was analyzed in a semi-quantitative score. Results: iNOS expression was found in cardiomyocytes, endothelial cells, infiltrating cells, and vascular smooth muscle cells. At the time of heart transplantation, the expression was significantly increased in the rejection group compared to the other groups. This increase was even more pronounced in week 2. Conclusions: The present study shows that an increased iNOS expression at the time of heart transplantation could precede an acute rejection in the later postoperative course. Thus, measurements of iNOS expression may be of predictive value for an increased rejection risk and therefore offer the possibility of earlier therapeutic intervention.

Key Words: Heart transplantation • Rejection iNOS expression


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Despite recent advances in the management of chronic heart failure by mechanical circulatory support, heart transplantation remains the optimal treatment option in these patients. The excellent 1-year survival rates of 85% and 5-year survival rates of more than 70% are mainly achieved by effective immunosuppressive strategies [1].

Nevertheless, early rejection episodes, especially in the first postoperative year, limit the long-term results [2]. However, there is still an ongoing debate, if early rejection episodes are responsible for the development of accelerated transplant arteriosclerosis.

Ischemia and reperfusion during heart transplantation cause damage to cardiomyocytes and endothelial cells. Free oxygen radicals generated by iNOS are widely accepted to be responsible for ischemic injury. As part of a non-specific defence system, NO is involved in inflammatory processes of the cardiovascular system [3]. Increased iNOS expression on cardiac tissue may represent a more intensive tissue injury during ischemia and reperfusion in heart transplantation.

NO is mainly produced by the inducible NO synthase (iNOS) using L-Arginine as a precursor [4]. iNOS belongs to the family of NO synthases including inducible (iNOS), endothelial (eNOS), and neuronal NO synthase (nNOS). It can be stimulated by endotoxins or cytokines and it was detected in inflamed tissue [3–6].

In addition, previous studies showed an increased expression of iNOS and iNOS-mRNA in areas of rejection (acute and chronic) and in apoptosis [7]. There is also evidence that it is involved in myocardial depression in sepsis [3].

Routine endomyocardial biopsies remain the gold standard in the detection of post-transplant rejection episodes. Nevertheless, the early identification of patients with an increased risk of rejection is desirable. The aim of this study was, therefore, to test the hypothesis that increased iNOS expression in early postoperative endomyocardial biopsies correlates with rejection or infection episodes in the later postoperative course. The question is if iNOS expression on cardiac tissue can serve as a marker for later rejection episodes. The earlier identification of patients at risk would allow earlier therapeutic interventions and help to avoid further complications as well as ameliorate the long-term course.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1 Patients
In this retrospective study, 36 heart transplantation recipients, transplanted between 1996 and 2004, were included on condition that a complete 1-year follow-up was available. They were divided into three sub-groups:

Group 1: 12 recipients with a clinically uneventful postoperative course (57 ± 5 years, 11 male);
Group 2: 12 recipients with cardiac or systemic infection, detected by histology, immunohistochemistry, and/or serology (49 ± 15 years, 10 male);
Group 3: 12 patients with acute rejection grade 2R ISLHT, detected by histology (55 ± 10 years, 9 male)

These patients had scheduled follow-up endomyocardial biopsies during transplantation, before implantation, and in the first two postoperative weeks. The mean age of the recipients is 54 ± 10 (MW ± SEM) years. Eighty-three percent were male, the mean donor age was 35 ± 15 years, and the mean ischemic time was 183 ± 40 min. All patients received a standard immunosuppressive protocol with anti-thymocyte globulin, cyclosporine A (CsA), azathioprine, and prednisone. The three groups did not differ significantly in the CsA level during the first two postoperative weeks.

Group 1 first week: 216 ng/l, second week: 297 ng/l; group 2 first week: 179 ng/l, second week: 274 ng/l; group 3 first week: 249 ng/l, second week: 331 ng/l.

The amount of inotropic support on postoperative day 1 was not significantly different between the groups:

Group 1: 11/12 patients dobutamine 5 µg/kg/min, 6/12 adrenalin 0.15 µg/kg/min
Group 2: 10/12 patients dobutamine 4.5 µg/kg/min, 5/12 adrenalin 0.15 µg/kg/min
Group 3: 10/12 patients dobutamine 4.5 µg/kg/min, 4/12 adrenalin 0.1 µg/kg/min

The donor inotropic support was as follows:

Group 1: 5/12 patients dobutamine 4 µg/kg/min, 1/12 noradrenalin 0.25 µg/kg/min
Group 2: 1/12 patients dobutamine 0.3 µg/kg/min, 2/12 noradrenalin 0.4 µg/kg/min
Group 3: 0/12 patients’ dobutamine, 0/12 noradrenalin (p < 0.01).

Myocardial conservation during transplantation was routinely performed by gravity infusion with 3 l of HTK solution in 11–14 min (Custodiol®, Dr F. Köhler Chemie GmbH, Alsbach, Germany). The classification of rejection was performed under strict consideration of the working formulation of the International Society for Heart and Lung Transplantation. There were no statistically significant differences in the biopsy results between the groups: in the first postoperative week only one patient per group had a biopsy graded 1R. During the second week one patient in group 1 was graded 1R, in group 2 four patients were graded 1R, and in group 3 five patients were graded 1R.

The expression of iNOS was examined immunohistochemically. Biopsies from each patient at the three different time points were fixed in 4% formalin, dehydrated in ethanol, embedded in paraffin, and cut into serial sections of 4–5 µm.

2.2 Immunohistochemistry
A modified biotin streptavidin alkaline phosphatase method was used for the detection of iNOS. After binding of a primary marker antibody, iNOS is visualized by a naphthol phosphate/fast red reaction (DAKO®, Fast Red substrate system K999).

The paraffin-embedded sections were de-paraffined, rehydrated, and rinsed in boiling citrate buffer for better detection of iNOS. The samples were processed with a mixture of CAS block, bovine albumin, and {gamma}-venin (rate 3: 1:1) before incubation in a 1:400 dilution of polyclonal rabbit antibody (Affinity Bioreagents, Golden, USA) as primary antibody for detection of iNOS. Then the second block (PBS and goat serum 1:6) was applied on the sections prior to incubation with the second goat anti-rabbit antibody. To detect the antigen–antibody complexes, Fast Red (Sigma Chemie, München, Germany) was used. Counterstaining was done by using hematoxylin (DAKO, Glostrup, Denmark) with the sections covered by Glycergel (DAKO, Glostrop, Denmark) and cover slips. For positive controls tonsil tissue accordingly treated was used. As a negative control the primary antibody was replaced by rabbit serum diluted 1:500 with PBS.

2.3 Semi-quantitative analysis
The iNOS expression in cardiac myocytes, endothelial cells, and vascular smooth muscle cells was measured using a semi-quantitative scoring system from 0 to 3 with 0.5 increments at a light microscopic magnification of 200-fold. The sections were evaluated blind by two independent observers to avoid a systemic error. Infiltrating cells were counted quantitatively and correlated to the surface of the specimen.

2.4 Statistics
Results are given as mean values ± standard deviation, the median and standard error of the mean. The Friedman test, the Wilcoxon match pairs signed rank test, the Wilcoxon–Mann–Whitney U-test, and the Kruskal–Wallis test were used where appropriate. The statistical analysis was performed with the SPSS® 13.0 software. Values of p ≤ 0.05 were regarded as statistically significant and p ≤ 0.1 were regarded as a trend.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
Immunohistochemistry showed an expression of iNOS in right ventricular cardiomyocytes, endothelial cells, and interstitial cells. Occasionally, vascular smooth muscle cells were stained (Fig. 1 ).


Figure 1
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  		Fig. 1. (A) Immunohistochemical expression of iNOS in cardiomyocytes of a right ventricular endomyocardial biopsy (score 1); (B) immunohistochemical expression of iNOS in cardiomyocytes (score 2), endothelial cells (score 2), and vascular smooth muscle cells of a right ventricular endomyocardial biopsy; (C) immunohistochemical expression of iNOS in cardiomyocytes of a right ventricular endomyocardial biopsy (score 3); (D) immunohistochemical expression of iNOS-positive infiltrating cells of a right ventricular endomyocardial biopsy.

 
3.1 iNOS expression on cardiomyocytes (Fig. 2)
During implantation the expression of iNOS in cardiomyocytes of recipients in the rejection group was significantly elevated compared to recipients from the other groups (p ≤ 0.05). The values remained elevated during the first week after transplantation. During the second postoperative week, iNOS expression increased slightly in the uncomplicated group, but in the rejection group it further increased significantly. In the infection group, values, however, remained stable during follow-up. Thus, the expression in the rejection group was significantly more pronounced than in the other groups in the second postoperative week.


Figure 2
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  		Fig. 2. (A) Immunohistochemical expression of iNOS protein on cardiomyocytes at heart transplantation (HTx) and the first two postoperative weeks in the uncomplicated, the infection, and the rejection collectives (mean value ± standard deviation); (B) immunohistochemical expression of the iNOS protein on endothelial cells at heart transplantation (HTx) and the first two postoperative weeks in the uncomplicated, the infection, and the rejection collectives (mean value ± standard deviation); (C) number of iNOS-positive myocardium infiltrating cells at heart transplantation (HTx) and the first two postoperative weeks in the uncomplicated, the infection, and the rejection collective (mean value ± standard deviation); (D) number of iNOS-positive myocardium infiltrating cells at heart transplantation (HTx) and the first two postoperative weeks in the uncomplicated and the complicated collectives (mean value ± standard deviation).

 
3.2 iNOS expression on endothelial cells (Fig. 2)
iNOS expression on endothelial cells was on a level comparable to that of cardiomyocytes. The intensity of staining at the time of heart transplantation was significantly elevated (p ≤ 0.05) in the rejection group compared to the uncomplicated and infection groups. In the infection group, values increased in postoperative week 1 and decreased in postoperative week 2 to the initial level (non significant). In the uncomplicated and infection groups, the intensity of iNOS staining in endothelial cells was rather weak for all points in time of the investigation.

3.3 iNOS expression in interstitial cells (Fig. 2)
iNOS-positive interstitial cells per mm2 were also calculated. The number of iNOS-positive infiltrating cells in the uncomplicated group at the time of transplantation was very low (25 ± 31 cells/mm2) and changed only slightly in the first (42 ± 35 cells/mm2) and second (30 ± 27 cells/mm2) postoperative weeks.

The number of infiltrating cells in the infection and rejection groups was four times higher (infection group 109 ± 107 cells/mm2, rejection group 108 ± 71 cells/mm2). This difference was statistically significant (p < 0.05). In the first week after heart transplantation, the number of iNOS-positive infiltrating cells in the infection group decreased slightly (84 ± 78 cells/mm2). In the rejection group the number remained on the same level (115 ± 72 cells/mm2), only the difference between the uncomplicated group and the rejection group was significant (p ≤ 0.05). During postoperative week 2, the number of infiltrating cells in the rejection group was the same as at the time of heart transplantation (110 ± 95 cells/mm2). The number of infiltrating cells in the rejection group increased nearly double the starting value. Because of a large standard deviation, this difference was not statistically significant.

The recipients of the infection and the rejection groups were combined to form a complicated group. In this combined group, the number of infiltrating cells was significantly elevated (p ≤ 0.05) compared to the uncomplicated group. For the iNOS expression in cardiomyocytes, the results were similar but not statistically significant.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
In this study, we found iNOS protein using immunohistochemical methods on cardiomyocytes, endothelial cells, and infiltrating interstitial cells in the right ventricle of the heart. Very rarely was there staining of vascular smooth muscle cells. Furthermore, we analyzed iNOS expression in the case of an acute rejection episode graded 2R ISHLT. iNOS is expressed during acute rejection on cardiomyocytes and endothelial cells (Fig. 3 ).


Figure 3
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  		Fig. 3. (A) Hematoxylin–eosin stained endomyocardial biopsy of a rejection graded 2R ISHLT; (B and C) serial sections of this endomyocardial biopsy from the same patient showing iNOS expression during an acute rejection episode on cardiomyocytes. iNOS dilution (B) 1:100, (C) 1:200.

 
In this study, even at the time of transplantation, the expression of the iNOS protein in cardiac myocytes was elevated significantly in patients with later rejections compared to patients with normal course or with an infectious course. Staining intensity remained stable during the first postoperative week and rose in the second postoperative week. The staining of the endothelium was similar to the staining of the myocardium, but we found a decrease in the second postoperative week to the starting level.

These findings support the results of previous studies indicating that an acute rejection after heart transplantation is preceded by an elevated expression of iNOS protein in the allografts. Furthermore, our results show that even before an acute rejection developed clinically or histologically, elevated iNOS protein levels in cardiac myocytes and cardiac endothelial cells were found. Given the fact that acute rejection may lead to heart failure these findings are in line with a study by Fukuchi et al. who found elevated iNOS expression in the failing heart but not in normal controls [8]. However, in this aspect our study remains speculative, because due to the small number of patients, samples of failing hearts were not included in our study. Therefore, we draw the conclusion that a perioperative injury of the transplanted heart may lead to an increased oxidative stress. This oxidative burden may lead to an increased antigenity and predisposes the recipient to later rejection. Although the perioperative damage during brain death of the donor and explantation can only partly be influenced, better structural protection and less oxidative stress will probably result in a more favorable outcome.

There are no studies to be found in the literature that correlate a higher iNOS expression after heart transplantation with acute rejections in the later postoperative course. Only nitrate as a by-product of NO has been examined. Winlaw et al. found elevated nitrate concentrations shortly after transplantation in the urine of rats with later rejection episodes [9]. Also, Albrecht et al. could show these finding days before an acute rejection after renal transplantation in humans. However, the expression of iNOS had not been tested before the onset of a proven rejection. In this case, a clear increase of iNOS compared to controls was found [10].

Rejection episodes can be classified as an acute form, emerging during the first year after heart transplantation, and a chronic form beginning after the first postoperative year. The morphologic substrate of acute rejection episodes is an inflammatory infiltrate, an impaired contractile function of the heart and cardiomyocyte necrosis [11]. The gold standard in the detection of rejection is the endomyocardial biopsy [2]. Previous investigations have shown evidence for the involvement of vasoactive substances in rejection episodes as well as in infections [12,13,14]. Inflammatory reactions seem to play a major role in the pathogenesis of a variety of acute and chronic cardiovascular pathology. In this context, there is an ongoing debate about the role of iNOS [14].

The NO system obviously has a key function in the vasoregulatory processes. NO acts as a vasodilatator using cGMP. Higher concentrations were shown to inhibit enzymes in the oxidative cycle of the cell and were shown to be directly cytoxic by DNA injury [15]. A basal release of NO is important to maintain a normal myocardial function [16]. Nevertheless, under pathological conditions, such as sepsis or allograft rejection, it may also impair myocardial function [17,18].

Three enzymes have been described to produce NO from L-Arginine: nNOS (neuronal), eNOS (endothelial), and iNOS (inducible) [4]. iNOS is induced by cytokines, is independent of calcium and calmodulin, and has the potential to produce large quantities of NO [19]. In non-endothelial cells, iNOS is only expressed after activation with bacterial endotoxins or inflammatory cytokines [6].

iNOS-dependent NO production was found in acute rejection episodes after heart transplantation [20]. There is a body of evidence for the assumption that this phenomenon may be responsible for the depression of myocardial function and can trigger apoptosis [11,21]. On the other hand, there is an ongoing debate whether iNOS-dependent NO production is needed for an effective rejection reaction [22].

In septic patients, iNOS expression in the ventricular myocardium was found to be significantly elevated and the contractile function of the myocytes was altered [18]. In experimental animal studies of sepsis, iNOS inhibitors improved the survival of the animals significantly [3].

The aim of this study was to investigate if iNOS expression is detectable in the first 2 weeks after heart transplantation by immunohistochemical methods. Further, we wanted to know if the expression of the iNOS protein in the first 2 weeks after transplantation could be used to distinguish an uncomplicated course and a complicated course with infection or acute rejection, and if this finding could be used to improve the survival after heart transplantation.

As NO produced by iNOS plays a crucial role in the contractile dysfunction of myocardium and in the necrosis of cardiac myocytes in an acute rejection and, as the by-product of NO, nitrite can be found in greater amounts before an imminent rejection, as well as the fact that a rejection can be blocked by the NOS inhibitor aminoguanidine, we conclude that a higher expression of iNOS protein in paraffin samples shortly after heart transplantation can be a sign for an imminent rejection in the postoperative course [21,23–25].

In summary, iNOS is expressed in a variety of cardiac pathologies. It was also shown that iNOS has a potential role in the repair processes after heart transplantation. To improve survival rates after heart transplantation an early differentiation of these processes in infection or rejection is necessary. One approach may be to define whether differences in the iNOS expression in endomyocardial biopsies from transplanted and non-transplanted normal hearts can help to detect these complications earlier.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In our opinion, the routine detection of the iNOS protein by immunohistochemistry in paraffin-embedded sections taken after heart transplantation could probably be used to find patients with postoperative rejection periods before they take place. At least this practice could be used to predict a complicated postoperative course from an uncomplicated postoperative course. Other factors influencing the results, such as donor intensive care therapy or immunosuppression, should be taken into account as well.


   Footnotes
 
1 These authors equally contributed to the preparation of this manuscript. Back


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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