© 2006 European Society of Cardiology
Thalidomide attenuates the development of fibrosis during post-infarction myocardial remodelling in rats
a Research Institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo N-0027 Oslo, Norway
b Institute for Surgical Research, Rikshospitalet University Hospital, University of Oslo N-0027 Oslo, Norway
c Department of Cardiology, Ullevål University Hospital Norway
d Section of Endocrinology, Rikshospitalet University Hospital, University of Oslo N-0027 Oslo, Norway
e Section of Clinical Immunology and Infectious Diseases, Rikshospitalet University Hospital, University of Oslo N-0027 Oslo, Norway
f Medical Department, Diakonhjemmet Hospital Oslo, Norway
* Corresponding author. Tel.: +47 23 07 36 29; fax: +47 23 07 36 30. E-mail address: arne.yndestad{at}klinmed.uio.no
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Background: Inflammation plays a pathogenic role in the development of heart failure (HF). The aim of this study was to examine the effect of treatment with the immunomodulating drug thalidomide in a rat model for post-myocardial infarction (MI) HF.
Methods: Rats were subjected to MI by left coronary artery ligation or sham-operated. Seven days after surgical intervention rats were randomised to treatment with thalidomide or vehicle for 8 weeks.
Results: Our main findings were: (i) thalidomide treatment did not affect cardiac function or the hypertrophic response, as determined by haemodynamic measurements and heart chamber weights, respectively. (ii) HF rats treated with thalidomide had a minor reduction in septum and relative wall thickness (p<0.05), indicating an anti-remodelling effect. (iii) Thalidomide appeared to have immunostimulatory effects on the myocardium as evident by increased MIP-1
gene expression (p<0.05). (iv) Treating HF rats with thalidomide reduced myocardial collagen content, as assessed by markedly decreased levels of hydroxyproline (
40% reduction; p<0.05), accompanied by lower TGF-β1 gene expression (p<0.05).
Conclusion: Although thalidomide had no effect on cardiac function, our results suggest that intervention with thalidomide may have beneficial effects in post-MI HF by attenuating collagen accumulation and development of myocardial fibrosis.
Key Words: Heart failure • Myocardial infarction • Inflammation • Fibrosis • Cytokine • Intervention
Received August 23, 2005; Revised January 3, 2006; Accepted February 8, 2006
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Heart failure (HF) is associated with persistent immune activation and inflammation. This notion is based on numerous studies showing that patients with HF have elevated levels of inflammatory cytokines such as tumor necrosis factor (TNF)P, interleukin (IL)-1 and monocyte chemoattractant protein (MCP)-1 in plasma/serum, in circulating leukocytes and also in the failing myocardium, with increasing levels according to disease severity [1,2]. Moreover, a growing body of evidence indicates that these inflammatory mediators may have pathogenic effects on the myocardium by influencing contractility, growth, fibrosis and apoptosis, all the latter contributing to the continuous myocardial remodelling process [3]. These findings collectively suggest that cytokines and other inflammatory mediators may represent new targets for therapy in HF [1].
Thalidomide was originally marketed as a sedative and anti-emetic drug, but was withdrawn due to severe teratogenic effects [4]. Subsequently, thalidomide has been recognized to possess potent immunomodulatory, anti-angiogenic, and anti-oncogenic properties, and diseases such as erythema nodosum leprosum, rheumatoid arthritis, and myelomatosis are currently being treated with this drug [4]. Recent data have also suggested a role for thalidomide in the management of chronic HF [5-7]. However, the mechanisms for the salutary effects of thalidomide in the various disorders are far from clear. Furthermore, contradictory results have been reported concerning its anti-inflammatory effects in vivo [4,8-10]. Other properties of thalidomide could also be of importance in relation to its potential role in HF, such as effects on fibrosis and matrix degradation [8,11]. On the other hand, the anti-angiogenic properties of thalidomide, inhibiting the formation of new vessels, could potentially be harmful, particularly in ischaemic heart disease [7].
To further elucidate the potential role of thalidomide in the management of HF, we performed a study examining the effects of thalidomide on myocardial remodelling, inflammation, and development of fibrosis in a rat model of post-myocardial infarction (MI) HF.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1. Experimental procedure and study protocol
Male Wistar rats (
330 g) were subjected to left coronary artery ligation or sham operation during isoflurane anesthesia (1% isoflurane in a mixture of one-third O2 and two-thirds N2O) as previously described [12]. Mortality of the rats with MI was 40 % during the first 48 h after surgery. Seven days after the surgical procedure, 27 MI rats and 11 sham-operated rats were randomised to daily treatment with thalidomide (Sauramide®, Penn Pharmaceutical Services, UK; 100 mg kg– 1 PO; 7 sham rats and 11 MI rats) or vehicle (ground nut oil; 6 sham rats and 13 MI rats). Thalidomide was suspended in ground nut oil (vehicle) and administered by gavage once daily. The treatment was continued for 8 weeks. After randomisation to treatment groups, 3 rats died (2 vehicle-treated and 1 thalidomide-treated). The investigation conforms to institutional guidelines and the Guide for Care and Use of Laboratory Animals published by the US National Institutes of health (NIH Publication No. 85-23, revised 1996). The investigators performing haemodynamic measurements and echocardiographic examination were blinded to the randomisation protocol.
2.2. Haemodynamic measurements
Arterial blood pressure, left ventricular (LV) end-diastolic pressure (LVEDP), and systolic pressure (LVSP) as well as peak positive and peak negative first derivatives of the LV pressures (+dP/dt and –dP/dt) were measured under isoflurane anesthesia using a 2F micromanometer-tipped catheter (model SPR-407, Millar Instruments, TX). The haemodynamic measurements were performed >12 h after the last dose of thalidomide or vehicle to minimize a putative acute effect of thalidomide on haemodynamic parameters.
2.3. Echocardiographic examination
Transthoracic echocardiography was performed immediately after the haemodynamic measurements as previously described using the fully digital Vingmed System FiVe (GE Vingmed Ultrasound, Horten, Norway) and a 10 MHz linear array transducer [13]. 2D-guided M-mode recordings of the LV in the short-axis view at the level of the papillary muscle were obtained, and interventricular septum (IVST) and posterior wall thickness (PWT) at end-diastole (IVSEDT and PWEDT, respectively) and at end-systole (IVSEST and PWEST, respectively) were measured. LV internal end-diastolic (LVEDD) and end-systolic diameters (LVESD) were recorded as the largest anterio-posterior diameter outside the infarcted area. LV fractional shortening (FS) and relative wall thickness (RWT) were calculated using the following formulas: FS (%)=[(LVEDD–LVESD)/LVEDD]x100 and RWT=(IVST+PWT)/LVEDD, respectively.
2.4. Tissue sampling
After echocardiographic examination, rats were euthanized by excision of the heart. The atria, the right ventricular free wall, and the LV (LV free wall and interventricular septum) were separated and weighed. The LV was further processed separating the infarcted area, the non-infarcted LV free wall, and the interventricular septum. The infarcted area was weighed to estimate infarct size. The lungs, liver, and spleen were also dissected and weighed. The tissues were snap-frozen in liquid nitrogen and stored at –70 °C until used. The right tibia of each rat was isolated and the length was measured.
2.5. Analysis of gene expression
Total RNA was extracted from non-infarcted LV free wall (border zone to the MI) and interventricular septum (IVS) using Trizol and subsequently treated with DNase (RQ1 DNase; Promega, Madison, WI). Quantification of gene expression was performed using the ABI Prism 7000 (Applied Biosystems, Foster City, CA) as previously described [14]. Primers were designed using the Primer Express software version 2.0 (Applied Biosystems; see Table 1 for details). cDNA was prepared from 1 µg total RNA using the High Capacity cDNA Archive kit (Applied Biosystems). Real-time quantitative RT-PCR was performed using qPCR Master Mix for SYBR Green I (Eurogentec) and 300nM sense and anti-sense primers. All samples were run in triplicate. Melting point analyses were performed to confirm the specificity of the PCR. The relative standard curve method was used to calculate the relative gene expression. Gene expression of GAPDH was also analyzed by real-time RT-PCR and used for normalization.
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2.6. Hydroxyproline measurement
Hydroxyproline content of myocardial tissue was determined by using a modified Stegemann procedure [15]. Briefly, myocardial tissues were dried, weighed, and hydrolyzed in 6 N HCl at 100 °C for 24 h, followed by neutralization with 6 N NaOH. Chloramine-T reagent and Ehrlich's reagent solution were added and the samples were mixed and incubated at 60 °C for 30 min. The absorbency of the samples was read at 558 nm and the hydroxyproline concentration was assessed using a curve obtained from hydroxyproline standard solutions.
2.7. Statistical analyses
Data are given as mean±S.E.M. Comparisons between the groups were analyzed by Kruskal-Wallis test and subsequent analyses were performed with the Mann-Whitney test. Probability values are two-sided and considered significant when <0.05.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. Effects of thalidomide on myocardial hypertrophy
The effects of treatment with thalidomide on body, heart and organ weights are summarized in Table 2. As expected, the ratios of ventricular weight-to-tibial length were significantly increased in the HF-vehicle group as compared to sham-operated rats, demonstrating compensatory myocardial hypertrophy. However, thalidomide did not affect the hypertrophic response as no significant differences in cardiac chamber weights between the HF-thalidomide and the HF-vehicle groups were found.
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3.2. Effects of thalidomide on LV pressures and dimensions
Table 3 summarizes analyses of haemodynamic parameters and cardiac dimensions. There were no differences between the HF-thalidomide and the HF-vehicle groups with regard to haemodynamic parameters (MAP, LVSP, and LVEDP). However, when analyzing LV dimensions with echocardiography, some significant findings between these two treatment groups were revealed. Thus, while thalidomide treatment did not affect the LV diameter (i.e., LVEDD and LVESD), HF-thalidomide rats had a minor, though significant decrease in septum thickness (i.e., IVSEDT and IVSEST; Table 3, p<0.05) as compared to HF rats treated with vehicle, suggesting that thalidomide may attenuate myocardial remodelling processes. Moreover, the RWTED and the RWTES, expressing the relationship between thickness of the ventricular walls and the ventricular diameter, were also lower in HF-thalidomide than in HF-vehicle-treated rats (Table 3, p<0.05) substantiating the notion that thalidomide influences myocardial remodelling in HF.
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3.3. Effects of thalidomide on myocardial expression of fetal genes
To further examine the effects of thalidomide on myocardial remodelling, we analyzed the gene expression of atrial natriuretic peptide (ANP) and P-skeletal actin in the IVS and in the non-infarcted area bordering the infarction (border zone). Characteristic of post-MI remodelling, we found markedly upregulated expression of these fetal genes in the regions examined (Fig. 1). However, there were no differences in the expression of these genes between HF rats receiving vehicle or thalidomide.
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3.4. Effects of thalidomide on gene expression of inflammatory cytokines
Since thalidomide possesses anti-inflammatory properties, we examined whether thalidomide treatment altered myocardial gene expression of inflammatory cytokines. The myocardial expression of genes encoding IL-8, MCP-1, macrophage inflammatory protein (MIP)-1P and TNFP was significantly higher in untreated HF rats than in sham rats in all examined regions, illustrating an inflammatory response within the failing myocardium (Fig. 2). However, thalidomide did not reduce this induction of inflammatory cytokines. In fact, and somewhat surprisingly, HF-thalidomide rats had significantly increased gene expression of MIP-1P in the border area as compared to vehicle-treated HF rats (Fig. 2C, p<0.05). Also the gene expression of TNFP in the border area tended to be higher in rats receiving thalidomide (Fig. 2D, p=0.08). Thus, in contrast to the anticipated anti-inflammatory effects, thalidomide seemed to modestly enhance the inflammatory response within the failing myocardium in this rat model of post-MI HF.
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p<0.05 vs. HF-Veh.3.5. Effects of thalidomide on expression of genes related to fibrosis
Thalidomide has previously been shown to have anti-fibrotic effects [8]. Therefore, we examined the effects of thalidomide on the gene expression of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, and tissue inhibitor of metalloproteinases (TIMP)-1, all important actors in extracellular matrix remodelling and fibrosis development. The expression of these genes was as expected significantly elevated in both the IVS and in the border area of the post-MI HF rats, and notably, HF rats treated with thalidomide had significantly lower levels of TGF-β1 mRNA in the non-infarcted LV free wall (border area) as compared to vehicle-treated HF rats (Fig. 3A; p<0.05). In contrast, we did not find any effect of thalidomide on the gene expression of MMP-2 or TIMP-1 (Fig. 3B and C).
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3.6. Effects of thalidomide on myocardial hydroxyproline content
To further examine the possible effect of thalidomide on the development of fibrosis, we analyzed the levels of hydroxyproline in the border area and in the IVS. We found that HF rats treated with thalidomide had markedly decreased levels of hydroxyproline in the border area as compared to untreated HF rats (Fig. 4; 37% reduction, p<0.05), suggesting that thalidomide decreases the myocardial levels of collagen and, thus, could attenuate the development of interstitial fibrosis during post-MI remodelling and HF.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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In the present study we have examined the effects of thalidomide in a rat model of post-MI HF. Thalidomide treatment did not affect cardiac function as determined by haemodynamic measurements. Moreover, we did not find any effect of thalidomide on LV mass. However, thalidomide-treated HF rats had a modest but significant reduction in septum and relative wall thickness. Furthermore, treatment of HF rats with thalidomide reduced the myocardial collagen content, as assessed by decreased levels of hydroxyproline, accompanied by suppressive effects on TGF-β1 gene expression. Thus, although the results from this relatively small animal study will have to be interpreted with caution, our results may suggest that thalidomide could modulate the development of myocardial fibrosis.
The immunomodulating properties of thalidomide are complex and not fully understood. Thalidomide has been regarded as an anti-inflammatory and in particular an anti-TNF drug. This notion is primarily based on evidence presented in in vitro studies using monocytes and macrophages [16,17]. Furthermore, lowering of TNFP levels has also been suggested as a major mechanism for the beneficial effect of thalidomide in e.g., erythema nodosum leprosum [18]. However, no or even enhancing effects of thalidomide on TNFP levels have been reported in other in vivo studies [8,10], and it has become evident that thalidomide may also have immunostimulatory properties [17,19]. In such, thalidomide has been shown to be co-stimulatory for CD4+ and CD8+ T-cells, leading to an inflammatory Th1-type cellular immune response [17,19]. In the present study, we somewhat surprisingly found that thalidomide significantly enhanced the expression of MIP-1P and tended to increase TNFP expression within the failing myocardium. Interestingly, thalidomide was recently shown to upregulate MIP-1P in an animal model of herpes simplex virus-induced Behçet's disease [9], further suggesting enhancing effects of thalidomide on this CC-chemokine. Moreover, we have very recently showed increased plasma levels of TNFP during thalidomide therapy in human HF, additionally questioning the role of thalidomide as an anti-TNF drug [20].
The major finding in the present study was that treatment with thalidomide attenuated the development of myocardial fibrosis as assessed by decreased collagen content. Thus, rather than an anti-inflammatory medication, this study suggests that thalidomide may function as an anti-fibrotic agent. Cardiac fibrosis, involving increased quantity and remodelling of the extracellular matrix, is a hallmark of myocardial remodelling and has important functional consequences for the heart. First, the fibrosis may result in augmented mechanical stiffness contributing to myocardial dysfunction. Second, perivascular fibrosis may impair cardiomyocyte oxygen and nutrient availability, and the increased collagen content may also disrupt electronic connectivity between cardiomyocytes, leading to increased susceptibility to arrhythmias [21]. Thus, our finding that thalidomide attenuates the accumulation of collagen post-MI may potentially limit the deterioration of myocardial function and the progression of HF. On the other hand, an anti-fibrotic effect alone, without modulation of other remodelling processes, may not necessarily be beneficial. At least in short term, this effect could potentially contribute to increase thinning of the infarcted area with subsequent ventricular dilatation. In fact, we found that thalidomide treatment tended to increase the gene expression of ANP and P-skeletal actin, potentially reflecting increased ventricular wall stress and overriding counteracting mechanisms. However, although we were not able to detect any changes in cardiac performance after thalidomide treatment of HF rats, it is not inconceivable that such effects, related to its anti-fibrotic properties, could appear later in the course of HF. Interestingly, the documented beneficial effects of aldosterone antagonism on morbidity and mortality in patients with HF [22] have, at least partly, been attributed to a beneficial effect on myocardial fibrosis [23].
The mode of action for the anti-fibrotic effects of thalidomide in the present study is unclear, but may potentially involve several mechanisms. First, the attenuated fibrosis could be due to a direct effect of thalidomide on myocardial TGF-β1 gene expression, resulting in lower levels of a major stimulus for extracellular matrix remodelling [24]. Second, thalidomide may directly affect fibroblast proliferation and survival. Supporting the latter hypothesis, metabolites of thalidomide have been shown to suppress proliferation of embryonic fibroblasts in vitro [25]. Finally, it may be argued that the immunostimulatory effect of thalidomide may prove beneficial by contributing to decreased accumulation of extracellular matrix since a Th1-type immune response as promoted by thalidomide may inhibit collagen biosynthesis [17,26]. Notably, our findings relating to attenuated fibrosis (i.e., down-regulation of hydroxyproline and TGF-β) were only significant in the LV free wall bordering the infarcted area and not in the IVS. The reason for these differences is unclear, but may reflect that the modulated parameters in general are higher in the former area, possibly reflecting more dynamic and activated autocrine/paracrine system due to a higher wall stress and ischaemia in the MI border zone, making the parameters more susceptible for therapeutic modulation.
Recently, we showed that thalidomide had a beneficial effect on LV ejection fraction in patients with chronic HF, demonstrating a clinical potential for this treatment. Notably, this effect was more pronounced in patients receiving the highest thalidomide dosage, indicating a dose-response effect [20]. Due to differences in metabolism, it is hard to directly compare doses used in humans and in rodents. The dosing schedule in the present study (100mg/kg/day) was based on several other studies showing both immunomodulatory, anti-angiogenic and growth inhibitory effects in doses ranging from 50 to 200mg/kg/day [27,28]. A medium dose was chosen to minimize potential side effects. However, with the results from our clinical trial in mind, it is possible that a higher dosage of thalidomide could have produced better and clearer effects.
In conclusion, although thalidomide had no effect on cardiac function or LV mass, our results suggest that intervention with thalidomide may have beneficial effects by attenuating the accumulation of collagen and the development of myocardial fibrosis. This anti-fibrotic effect could potentially contribute to limiting development and progression of HF. However, although statistically significant, the findings during thalidomide therapy were rather modest and should be interpreted with caution. Future studies will have to further examine the immunostimulatory effects of thalidomide and determine the consequences of these actions for the suitability for thalidomide as a novel therapeutic option in HF. Such studies should also try to define the optimal dosage as well as the mechanisms of action of this medication more precisely.
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