Cardiovascular Research

Cardiovascular Research 2002 53(1):124-130; doi:10.1016/S0008-6363(01)00433-3
© 2002 by European Society of Cardiology

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Copyright © 2001, European Society of Cardiology

Reversible activation of nuclear factor-B in human end-stage heart failure after left ventricular mechanical support

Florian Grabellus^a,1, Bodo Levkau^b,1, Andrea Sokoll^b, Hendryk Welp^c, Christof Schmid^c, Mario C Deng^d, Atsushi Takeda^e, Günter Breithardt^f and Hideo A Baba^a,*

^aThe Gerhard-Domagk-Institute of Pathology, University of Münster, Domagkstrasse 17, 48149 Münster, Germany
^bThe Institute of Arteriosclerosis Research, University of Münster, Domagkstrasse 3, 48149 Münster, Germany
^cDepartment of Cardio-thoracic Surgery, University of Münster, Albert-Schweitzer Strasse 33, 48149 Münster, Germany
^dThe Heart Failure Center, Columbia University, New York, NY, USA
^eDepartment of Internal Medicine, Aoto Hospital, Jikei University, Tokyo, Japan
^fDepartment of Cardiology and Angiology, University of Münster, Albert-Schweitzer Strasse 33, 48149 Münster, Germany

^* Corresponding author. Tel.: +49-251-835-5446; fax: +49-251-835-5460 baba{at}uni-muenster.de

Received 14 March 2001; accepted 9 August 2001

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion References

 
Objective: Left ventricular assist devices (LVAD) have been used to ‘bridge’ patients with end-stage heart failure to transplantation. Although several reports have suggested that the native ventricular function recovers after long-term LVAD support, a process called ‘reverse remodeling’, the underlying biological mechanisms are still unknown. As the transcription factor nuclear factor-B (NF-B) has been shown to be active in the failing human heart, we examined whether its activity is altered under LVAD support, and may thus contribute to the dynamic process of ‘reverse remodeling’. Methods: The activity of NF-B was studied in 16 patients with end-stage heart failure (eight with dilated cardiomyopathy, six with ischemic heart disease, one with myocarditis, and one with congenital heart disease) before and after LVAD support by immunohistochemistry using an antibody against active NF-B. Gel-shifts for NF-B DNA-binding activity were performed with paired human myocardial tissue from four patients. The mean cardiomyocyte diameter before and after mechanical unloading was measured with an image analyzer system. Results: 15 patients out of 16 showed a significant decrease in the number of NF-B positive cardiomyocyte nuclei after LVAD support in the left ventricular myocardium. The NF-B DNA-binding activity also decreased after LVAD support as measured by gel-shift analysis. While the number of positive cardiomyocytes was significantly higher in the subendocardium than in the subepicardium at the time of LVAD implantation, this difference was no longer present at the time of LVAD explantation. The diameter of cardiomyocytes in the left ventricle decreased significantly as a parameter of structural reverse remodeling. Conclusion: LVAD support decreases the extent of NF-B activation in failing human hearts, suggesting that NF-B may be involved in the process of ‘reverse remodeling’.

KEYWORDS Heart failure; Hypertrophy; Myocytes; Remodeling; Signal transduction

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion References

 
The limitation of donor hearts for transplantation has promoted the establishment of alternative treatments such as the implantation of left ventricular assist devices (LVAD) [1]. LVAD is used in patients with end-stage heart failure to ‘bridge’ them to transplantation. This device increases cardiac output, normalizes systemic blood pressure, and improves end-organ function [2]. LVAD has also been shown to reverse the complex process of chronic left ventricular remodeling, so that some patients could be weaned from the device without the need for heart transplantation [3]. This process has been termed ‘reverse remodeling’. Morphologic studies have described a decrease in mean cardiomyocyte diameter, cell volume, length, and width after mechanical support [4]. However, the molecular mechanisms underlying these changes are still unknown, although individual genes such as atrial natriuretic peptide/brain natriuretic peptide (ANP/BNP) [5], interleukin-6 (IL-6) [6] and tumor necrosis factor- (TNF-) [7] have been shown to be reversibly regulated under LVAD. Recently, several studies have observed apoptotic cell death in terminally failing human hearts [8], and the expression of apoptosis-associated genes has been shown to be altered under mechanical support [9]. The transcription factor nuclear factor kappa B (NF-B) is a crucial regulator of genes involved in cellular protection against apoptosis [10], and activation of NF-B has recently been observed in the myocardium of patients with congestive heart failure [11].

As a potent regulator of gene expression during immune and inflammatory responses, NF-B is localized in the cytoplasm in a complex with inhibitory proteins (IBs), which mask its nuclear localization signal and prevent its translocation to the nucleus. Site-specific phosphorylation and proteasomal degradation of IBs after a specific stimulus allows NF-B to translocate to the nucleus, bind to DNA, and activate the transcription of specific genes.

In this study, we examined the activity of NF-B in end-stage heart failure before and after mechanical support. We provide evidence that NF-B is dynamically regulated after LVAD, and that a gradient of reversible NF-B activation is present between the subendocardial and subepicardial area.

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion References

 
2.1 Patients
We obtained left ventricular specimens from 16 patients with end-stage heart failure who underwent LVAD implantation as a bridge to transplantation. Myocardial tissue was collected from the same patient from the left ventricular apex at the time of LVAD placement and LVAD removal, respectively. Eight patients suffered from dilated cardiomyopathy (DCM), six from ischemic heart disease (IHD), one patient had myocarditis (MTS) and one had Tetralogy of Fallot (TOF). The mean age of the patients was 41 years (median 43, range 24–57 years), and the mean duration of mechanical unloading was 139 days (median 88, range 14–309 days). Myocardial tissue of four further patients with end-stage heart failure due to dilated cardiomyopathy were investigated with gel-shift assays. At the time of LVAD implantation all 16 patients received intensive medical treatment consisting of an individual combination of angiotensin-converting enzyme inhibitor, digoxin, diuretics and beta-blocker. After LVAD, all 16 patients remained on the same drug regimen as before LVAD. The investigations conform with the principles outlined in the Declaration of Helsinki.

2.2 Immunohistochemistry and histologic examination
Cross-sections through the left ventricular wall were fixed immediately in buffered 4% formalin, embedded in paraffin and cut in 5 µm sections. Immunostaining was performed with an activation-specific monoclonal antibody against the p65 subunit of NF-B (clone 12H11, Boehringer Mannheim, Germany). The slides were autoclaved for 10 min, dewaxed and rehydrated. The antibody was applied in a humidified chamber at 4°C for 16 h in a concentration of 1:25 in 0.6% bovine serum albumin, followed by a rabbit anti-mouse bridging antibody (1:30 in PBS; 30 min at room temperature; Dako) and a polyclonal mouse APAAP complex (1:100 in RPMI; 60 min at room temperature; Dianova). The enzyme reaction was developed with new fuchsin-containing levamisol (Sigma) and counterstained with hematoxylin. An isotype-matched IgG-antibody served as negative control. Cross-sections from the left ventricular wall were separated into a subendocardial and a subepicardial area. Within each region, 100 cardiomyocyte nuclei were examined for NF-B-immunopositivity at a final magnification of x400. Each cross-section was examined independently by two blinded observers on two separate occasions. The correlation of NF-B-positive cardiomyocyte nuclei per 100 cardiomyocyte nuclei examined in one cross-section shows a coefficient of R=0.657 in the subendocardial and R=0.576 in the subepicardial region, respectively, at the time of LVAD implantation between observers 1 and 2. After LVAD support, the coefficient between both observers was R=0.856 subendocardially and R=0.641 subepicardially.

By support of an image analyzer system (VIDAS 25, Zeiss) the mean diameter of left ventricular cardiomyocytes was determined on PAS-stained sections. In each sample, 300 cardiomyocytes were evaluated on the nucleus level using the two-point distance function of the system.

2.3 Electrophoretic mobility shift assay
Gel shifts were performed as described [12]. In brief, frozen myocardial samples were ground to a fine powder under liquid nitrogen and suspended in buffer A (10 mM Hepes, pH 7.9, 10 mM KCl, 1.5 mM MgCl₂, 0.1% NP-40, 1 mM PMSF, 0.5 mM DTT, 10 µg/ml aprotinin and leupeptin) and incubated on ice for 20 min. The nuclei were separated by centrifugation at 12,000xg for 5 min at 4°C, and the nuclear pellet resuspended in buffer C (20 mM Hepes, pH 7.9, 420 mM NaCl, 1.5 mM MgCl₂, 0.2 mM EDTA, pH 8.0, 25% glycerol, 0.5 mM DTT, PMSF, aprotinin, and leupeptin) and incubated for 20 min on ice. The lysed nuclei were centrifuged twice for 5 min at 4°C in a microfuge, supernatants were diluted in a 2:3 ratio with buffer D (20 mM Hepes, pH 7.9, 50 mM KCl, 0.2 mM EDTA, 20% glycerol, PMSF, aprotinin, leupeptin) and protein content determined using the Biorad BCA assay method. A double-stranded oligonucleotide containing the consensus NF-B- and Oct-1 DNA-binding sites (Santa Cruz), respectively, was end-labeled using [³²P]ATP and 50 000 cpm of labeled probe were incubated with 25 µg of nuclear extracts in 10 mM Tris, pH 7.5, 1 mM DTT, 1 mM EDTA pH 8.0, 1% NP-40, and 0.05 µg/µl of Poly dIdC.dIdC (Boehringer Mannheim, Germany) at room temperature for 20 min. The samples were run on a 5% non-denaturing acrylamide gel. The gels were dried and bands detected by autoradiography.

2.4 Statistical analysis
All data were calculated with the software program SPSS 9.0 for windows. Continuous data of NF-B positive nuclei and cell diameter before and after LVAD implantation were tested for significance with the Wilcoxon matched-pair-test.

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion References

 
To examine the effect of LVAD support on NF-B activity, we performed immunohistochemistry on myocardial cross sections from the left ventricular apex of patients with end-stage heart failure using an antibody which recognizes the active p65 subunit of NF-B. Samples from each patient were examined both at the time of LVAD placement and LVAD removal (matched samples) (Table 1).

View this table: [in this window] [in a new window]   Table 1 Patient characteristics

 
In 15 out of the 16 patients, the number of cardiomyocyte nuclei positive for active NF-B decreased dramatically after mechanical unloading (Fig. 1A and B). In all cross-sections examined, the predominant cell type immunopositive for active NF-B were cardiomyocytes. Endothelial cells of the endocardium and of the intramural vessels were also positive, while interstitial cells were predominantly negative (Fig. 1A and B). To exclude that the standard anti-rejection therapy with 1 g prednisolone routinely given to all patients 2–6 h prior to transplantation, has an effect on NF-B [13], we compared the levels of NF-B immunopositivity in the myocardium of all 16 patients at LVAD implantation with seven explanted hearts from patients with terminal heart failure who also received 1 g prednisolon prior to transplantation but were not supported by LVAD. Both groups had comparable percentage of NF-B positive nuclei with a median percentage of NF-B positive nuclei of 82.0 in the non-LVAD supported hearts and 77.7, respectively, in the supported group (data not shown). Therefore, prednisolon does not have any effect on the regulation of NF-B we observed during LVAD support.

View larger version (73K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 (A) Immunolocalization of activated NF-B in cardiomyocyte nuclei (red color, double arrows) in the subendocardial area of an end-stage failing heart due to dilated cardiomyopathy with only few NF-B negative nuclei (arrow). Endocardial endothelial cells are activated as well (arrowhead) x200. (B) Tissue from the same heart at LVAD explantation with negative NF-B nuclei in cardiomyocytes (arrows) and endocardial cells (endo, arrowhead) x200.

 
To test whether the immunoreactivity for active NF-B correlates with its DNA-binding activity, we performed gel-shift assays with nuclear extracts from left ventricular myocardial tissue acquired before and after LVAD from patients with end-stage heart failure due to DCM. In all four patients examined, the DNA-binding activity of NF-B was substantially decreased after LVAD-support (Fig. 2A), confirming the immunohistochemical results. The DNA-binding activity was specific for NF-B, as adding a 100-fold excess unlabelled consensus NF-B almost completely inhibited binding to DNA, while a 100-fold excess of unlabelled unrelated sequence had no effect on DNA binding (Fig. 2B). In addition, gel-shift analysis performed for the unrelated DNA binding protein Oct-1 in the same samples showed a moderate increase after LVAD (Fig. 2C), arguing for a differential regulation of transcription factors during LVAD support.

View larger version (61K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 (A) Gel-shifts for NF-B's DNA-binding activity on myocardial tissue from four patients at the time of LVAD implantation (pre-) and LVAD explantation (post-), respectively. Arrow indicates the mobility of the NF-B complex. (B) Gel-shifts for NF-B were performed with matched samples from patient 2 (pre- and post-LVAD, lanes 1 and 2). Adding a 100-fold excess of unlabelled specific NF-B consensus oligonucleotide (s) to the pre-LVAD sample almost completely abolished DNA-binding (lane 3), while addition of a 100-fold excess of unlabelled non-specific oligonucleotide (ns; p53mut consensus sequence) had no effect on DNA-binding (lane 4). (C) Gel-shifts for Oct-1 were performed on matched samples from patients 1 and 2 pre- and post-LVAD (same samples as in Fig. 2A). Arrow indicates the mobility of the Oct-1/DNA-complex.

 
To quantify the observed differences, we performed statistical analyses of the matched samples using the Wilcoxon matched-pair-test. At the time of LVAD implantation, the median percentage of NF-B positive nuclei was 77.7 (range 44.7–91.5), while it decreased approximately twofold to 33.4 (range 4.0–78.7) after LVAD support (P<0.001) (Fig. 3A). There was a gradient in the myocardial activation of NF-B at the time of LVAD implantation, with a significantly higher activation of NF-B in the subendocardium than in the subepicardium (P<0.038) with a median percentage of NF-B positive nuclei of 80.0 (range 28.5–95.5) versus 75.5 (range 41.0–88.0), respectively (Fig. 3B). After unloading, this gradient was no longer present.

View larger version (38K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 (A) Effect of LVAD support on cardiomyocyte NF-B activity. Box plots contain the median (black bold horizontal bar) as well as the 25th and 75th percentile (fine horizontal bar). (B) Difference of NF-B activity between subendocardial and subepicardial area. (C) NF-B activity in failing myocardium dependent on the underlying cause. (D) Effect of LVAD support on left ventricular cardiomyocyte diameter.

 
Patients with DCM showed a significant decrease of NF-B activation after LVAD support: median of 70.7 (range 56.7–84.5) versus median of 34.5 (range 5.2–78.7) (P<0.025). A similar decrease in NF-B immunoreactivity was observed in patients with IHD (from 81.9 pre-LVAD (range 44.7–91.5) to 36.1 post-LVAD (range 16.5–58.2) (P<0.028)). Although the number of NF-B-positive nuclei was substantially lower after LVAD in patients with myocarditis and Tetralogy of Fallot, no statistical analysis was possible because of the limited number of patients (Fig. 3D).

As a parameter of structural reverse remodeling, we determined the left ventricular cardiomyocyte diameter before and after LVAD. The median of the cardiomyocyte diameter at the time of LVAD implantation was 26.7 µm with a 25% percentile of 22.6 µm and a 75% percentile of 33.9 µm. After LVAD support, the diameter decreased significantly (P<0.011) to a value of 23.87 µm with a 25% percentile of 22.54 µm and a 75% percentile of 26.0 µm (Fig. 2D).

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion References

 
In the present study, we demonstrate abundant activity of NF-B in cardiomyocytes in the failing human heart. We show this activity to be dramatically decreased after mechanical unloading with LVAD. Our findings suggest that activation of NF-B is a specific and reversible functional response of the heart to the molecular signals induced by overload.

Little is known about the genes and molecular mechanisms involved in ‘reverse remodeling’. We and others have previously shown downregulation of metallothionein [14], heme oxygenase-1 [15], IL-6 [6], and TNF- [7] under LVAD support, while other studies have described upregulation of anti-apoptotic genes such as Bclx_L [9]. While activation of NF-B has previously been observed in heart failure [11], no data is currently available on the transcriptional regulation under LVAD in humans. In an animal model of ventricular unloading, reactivation of ‘fetal’ genes has been suggested to play a role in the adaptation process, but the level of transcription factors such as MEF2 and GATA4 did not change [16]. We identify NF-B as the first transcription factor that is negatively regulated under LVAD. As NF-B transcriptionally regulates genes such as TNF-, IL-6 and heme oxygenase-1 [13,17], the specific changes in their expression in failing and supported human hearts may result from changes in the activity of NF-B. Thus, NF-B may regulate a subset of genes associated with ‘reverse remodeling’.

The stimuli leading to NF-B activation in the failing heart and to its inactivation after LVAD-mediated unloading, respectively, are still unknown. However, we have observed a gradient in the activity of NF-B in the failing heart with higher activity in the subendocardium than in the subepicardium, which disappears after LVAD. The subendocardium is the least well-perfused region of the failing myocardium and the most vulnerable region to reduction of blood supply due to abnormally high wall stress under circumstances of unnatural overload [18]. The resulting local tissue hypoxia may contribute to the high NF-B activity we observe in the subendocardium, since hypoxia has been shown to activate NF-B [19]. A similar transmural gradient has been observed previously for ANP/BNP [5], cyclooxygenase-2 [11], metallothionein [14] and heme oxygenase-1 [15], some of which are transcriptionally regulated by NF-B. LVAD decreases the ventricular filling pressure as well as wall stress, and improves myocardial O₂-supply most effectively in the subendocardium. This correlates with our observation of a decrease of cardiomyocyte hypertrophy specially in the subendocardial area [14], which is the region with the greatest reduction of wall stress. In addition, myocardial hypertrophy appears to correlate with increased NF-B DNA binding activity in an experimental model of isoproterenol-induced hypertrophy in the rat heart [20]. Thus, reduction of local tissue hypoxia and hypertrophy after LVAD may result in decreased NF-B activity.

NF-B is a transcription factor which plays a crucial role in the regulation of genes involved in the protective response against cell stress and apoptosis. Therefore, its activation in the failing human heart may reflect the attempt of the stressed myocardium to protect itself against potentially deleterious conditions such as unnatural overload. In conclusion, our data show that NF-B is activated in the failing myocardium and that this activation is reversed during LVAD support, suggesting that NF-B may be involved in the process of ‘reverse remodeling’.

Time for primary review 27 days.

	Acknowledgements

 
The technical assistance of B. Naber, K. Kloke, B. Schulte, and M. Wolters is gratefully acknowledged. This work has been supported in part by the DFG and IZKF (to H.A.B.) and by Project B5 from SFB 1754 of the DFG (to B.L.).

	Notes

 
¹ The first two authors have contributed equally to this work.

	References

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion References

 

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