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European Journal of Heart Failure 2006 8(3):278-283; doi:10.1016/j.ejheart.2005.09.008
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© 2005 European Society of Cardiology

Influence of ACE-inhibition and mechanical unloading on the regulation of extracellular matrix proteins in the myocardium of heart transplantation candidates bridged by ventricular assist devices

Hendrik Miltinga,*, Astrid Kassnera, Latif Arusoglua, Helmut E. Meyerb, Michel Morshuisa, Ramona Brendela, Bärbel Klaukea, Aly El Banayosya and Reiner Körfera

a Ruhr-Universität Bochum, Herz-und Diabeteszentrum NRW, Klinik für Thorax-und Kardiovaskularchirurgie, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung Georgstr. 11, D-32545 Bad Oeynhausen, Germany
b Medizinisches Proteom-Center (MPC), Universitätsstr. 150, D-44801 Bochum, Germany

* Corresponding author. Tel.: +49 5731 97 3510; fax: +49 5731 97 2476. E-mail address:hmilting{at}hdz-nrw.de (H.Milting).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 
Background: Whether adverse structural changes in the myocardium due to remodelling can be reversed by ventricular assist device (VAD) support in patients with end-stage heart failure is controversial.

Aims: To investigate the effect of VAD support on the extra-cellular matrix.

Methods: We analysed the collagen content in terminal failing ventricles of VAD-patients and donor hearts using 4-hydroxyproline for total collagen and real time RT-PCR for fibronectin (FN), collagen I alpha 1 (Col1A1), III alpha 1 (Col3A1) and TGF beta 1 analysis.

Results: Compared to donor hearts we found similar increases in Col1A1 and TGF beta1 but not Col3A1 and FN mRNAs, which were similar in the myocardium from patients receiving a VAD or heart transplant. However, patients receiving ACE-I during VAD-support had lower Col1A1 mRNA content at transplantation. The total collagen content was not influenced by mechanical unloading or by ACE-I medication.

Conclusion: Mechanical unloading by VAD does not reduce the collagen content of the terminal failing ventricle possibly due to increased TGF beta1 levels. However, Col1A1 production may be reduced by ACE-I medication during VAD support.

Key Words: Extracellular matrix • Ventricular assist device • Mechanical unloading • TGF beta1 • Collagen • Reverse remodelling

Received August 27, 2004; Revised September 27, 2005; Accepted September 27, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
Ventricular assist devices (VAD) are used to bridge patients suffering from endstage heart failure to transplantation. VADs can also induce reverse left ventricular remodelling, leading potentially, to recovery of ventricular function. A hallmark of myocardial remodelling is the deposition of interstitial extracellular matrix (ECM) proteins and fibrosis [1] and VADs could reduce fibrosis and collagen content. We [2] and others [3] found no change of the total collagen content, based on 4-hydroxyproline (4OH-P) determinations, in explanted hearts after VAD support, whereas Bruckner et al. reported a dramatic reduction (about 72%) of the total collagen by histological examination of tissue slides [4-6]. However, little is known about the influence of therapeutic interventions for heart failure during VAD unloading on collagen I alpha 1 (Col1A1), collagen III alpha 1 (Col3A1) and fibronectin (FN) mRNA expression, its relation to the total collagen content in the ventricular wall and to transforming growth factor beta 1 (TGF beta1) expression in this group of patients.

Accordingly, we investigated the effects of VADs and angiotensin converting enzyme inhibitors (ACE-I) on the extra-cellular matrix of patients undergoing VAD implantation and at the time of heart transplantation.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Paired left ventricular muscle samples were collected at the time of VAD implantation and later from the same patient at the time of heart transplantation. The samples representing transmural tissue without macroscopic signs of fibrosis were immediately frozen in liquid nitrogen and stored at –80 °C until analysis. Myocardial samples were also obtained from donor hearts, which could not be transplanted for technical reasons and were used for heart valve grafting in our centre (see Table 1 for clinical data of patients).


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  		Table 1 Clinical data at the time of VAD-implantation

 
All patients investigated were from the transplant program at the Heart and Diabetes Centre NRW. The study conforms to the principles outlined in the Declaration of Helsinki. The study was approved by the local ethics committee and all patients gave informed consent.

2.2. Isolation of total RNA from myocardial samples
Isolation of total RNA was done using a commercial RNA isolation kit (RNeasy, Qiagen, Hilden, Germany) according to the manufacturers instructions with modifications. For RNA extraction, about 30 mg of myocardial tissue without macroscopic evidence of fibrosis was prepared. Eluted total RNA was quantified at 260 nm in triplicate and was tested for genomic DNA contamination by PCR without reverse transcription and consecutive agarose gel electrophoresis. Preparations without genomic DNA contamination were adjusted to 100 ng/µl and used for RT-PCR analysis.

2.3. Reverse transcription and real-time PCR
Reverse transcription of myocardial RNA samples was done using 250 ng total RNA and 50 units superscript II (Invitrogen, Netherlands) after random priming with hexamers. 2 µl of the reaction mixture was used for each real-time PCR analysis.

The mRNA of FN, Col1A1, Col3A1 and TGF beta1 were analysed by real-time PCR [7,8] on a LightCycler (Roche, Basel, Switzerland). Analysis using the fluorescence data from real time PCR was referred to the mRNA of glycerine-aldehyde-3-phosphate-dehydrogenase (GAPDH) as a housekeeping gene. Relative quantification was evaluated using Relquant 1.0 software (Roche, Basel, Switzerland). For relative quantification, coefficient files for efficiency correction of the PCR reaction of each gene were established using human cardiac muscle mRNA as a calibrator. Analysis data were given as relative units mRNA per GAPDH mRNA. All samples were analysed in triplicate and paired samples from implantation and transplantation of the VAD were analysed in the same PCR run.

Primers used: GAPDH forward 5' TGC ACC ACC AAC TGC TTA G 3', reverse 5' GAT GCA GGG ATG ATG TTC 3'; Col1A1 forward 5' GCT TCA CCT ACA GCG TCA CTG TCG 3', reverse 5' AGA GGA GTT TAC AGG AAG CAG ACA G 3'; Col3A1 forward 5' CCG ATG GGT TGC CAG GAT CCA TG 3', reverse 5' GAA GGG CAT TGT GCT GAA CTT GCG 3'; fibronectin forward 5' GAA CCA TCA AGC CAG ATG TCA GAA GC 3', reverse 5' TGC CAT GAT ACC AGC AAG GAA TTG GG 3'; TGF beta 1 forward 5' CGA CTA CTA CGC CAA GGA G 3', reverse 5' GAG AGC AAC ACG GGT TCA G 3'. PCR reaction was done using a commercial SYBR green Taq-DNA polymerase mixture (FastStart DNA Master SYBR Green I, Roche, Basel, Switzerland). Data acquisition was adjusted 1-2 °C below the melting temperature of the corresponding PCR product to exclude non-specific fluorescence but none was detected. The temperature profile of the PCR reaction was 95°/10 min for hot start and 95 °C/10 s, 60 °C/10 s, 72 °C/25 s for 40 cycles. All PCR products were validated using automated cycle sequencing (ABI310; Applied Biosystems, Foster City, USA) and melting curve analysis of each run.

2.4. Hydroxyproline determination
The collagen content of the myocardial free wall was determined as 4-hydroxyproline content by amino acid analysis as previously reported [2]. Briefly, two independent tissue samples without macroscopic signs of fibrosis of the left ventricular free wall were hydrolysed in 6M HCl, transformed to the phenylthiocarbamoyl- (PTC-) derivatives and separated by HPLC using amino acid standards for quantification. Analysis was done in duplicate for each sample. Data are given as percent mole of 4-hydroxyproline per mole of total aminoacids.

2.5. Statistics
Statistics were done using GraphPad Prism version 4.02. Paired samples were analysed by two-tailed Student's t-test, with p<0.05 as significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 References
 
Paired data for the amount of 4OH-P and the relative expression of Col1A1, Col3A1, FN and TGF beta1 mRNA with GAPDH mRNA as the reference are shown in Fig. 1a-e. The 4OH-P content, representing total collagen, was increased compared to non-failing donor hearts (NF) (Fig. 1e) [2]. There was more Col1A1 mRNA compared to NF at the time of VAD implantation but no difference for Col3A1 mRNA was observed (Fig. 1a and b). Mechanical unloading of the failing myocardium in heart transplantation candidates had little effect on measured variables.


Figure 1
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  		Fig. 1 Gene expression of extracellular matrix proteins in patients supported by ventricular assist devices. NF=non-failing donor hearts, VAD-IP=samples from VAD-implantation, VAD-HTx=samples from VAD-transplantation. Individual data pre and post VAD-support (grey dots) and corresponding means (black dots; ±SD) of implantation and transplantation samples respectively are shown. (a) Collagen I alpha 1 mRNA, (b) collagen III alpha 1 mRNA, (c) fibronectin mRNA, (d) TGF beta 1 mRNA, (e) total collagen content measured as 4-hydroxyproline content, (f) relationship of collagen I alpha 1 mRNA, collagen III alpha 1 mRNA and 4-hydroxyproline content; the collagen I alpha 1 mRNA correlates with the hydroxyproline content, whereas the collagen III alpha 1 mRNA does not.

 
Myocardial 4OH-P content was related to Col1A1 mRNA level (p<0.005, r2=0.19, Fig. 1f), as previously reported [9], but not Col3A1 mRNA (Fig. 1f). TGF beta 1 mRNA was higher in failing hearts compared to non-failing controls (p<0.05; Fig. 1d) but did not change with VAD therapy (Fig. 1d). TGF beta 1 is the most potent inductor of the Col1A1 gene known so far [10,11]. At the time of VAD-implantation the mRNA of Col1A1 and FN correlated with the TGF beta 1 mRNA content (Fig. 2).


Figure 2
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  		Fig. 2 Correlation of TGF beta 1 mRNA and collagen I alpha 1 mRNA (left) and fibronectin mRNA (right) supports data of the inducing activity of TGF beta 1 on the collagen I alpha 1 promotor [10] and fibronectin transcription [33], respectively.

 
3.1. Influence of ACE-I medication
Although the mean values of Col1A1 mRNA in paired myocardial samples obtained at implantation and transplantation were similar, the response was heterogeneous. Col1A1 mRNA was similar in paired samples amongst patients who had received ACE-I (p=0.67) but the Col1A1 mRNA content of myocardial samples obtained at transplantation were lower in those patients who had received ACE-I (n=15) during VAD-support compared to those who had not (n=11; p<0.05; Fig. 3). The total collagen content and TGF beta 1 mRNA were similar in those patients who had or had not received ACE-I. Thus, administration of ACE-I during VAD support appeared to reduce the level of Col1A1 mRNA, but had no detectable impact on the total collagen already present in the failing ventricle at the time of VAD-implantation.


Figure 3
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  		Fig. 3 Expression of extracellular matrix proteins at VAD-transplantation with (+ACE-I) or without (ACE-I) angiotensin converting enzyme inhibition (ACE-I) during VAD support. ACE-I medication reduces the collagen I alpha 1 mRNA (p<0.05), but does not significantly reduce fibronectin mRNA, TGF beta 1 mRNA or the total collagen content either.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
Structural remodelling of the failing myocardium, leading to cardiomyocyte loss, an increase in interstitial collagen and impaired systolic and diastolic function, is a key determinant of the clinical outcome in chronic heart failure (CHF) [9,12]. Collagen functions as a supporting scaffold and anchor for the coordinated contraction of cardiomyoctes and represents about 85% of the heart's ECM [6,13,14]. Consequently, changes in collagen cross-linking may have profound effects on the force development of murine papillary muscles and lead to slippage and ventricular dilatation [12,15-17].

Factors regulating collagen are diverse [10] and include matrix metalloproteinases [18-25], cytokines [26], growth factors [27] and mechanical strain [28,29]. Col1 is primarily regulated at the level of transcription [10] and is related to total collagen content [9]. The mean mRNA amounts of the major ECM proteins Col1A1, Col3A1 and FN were not regulated during ventricular unloading in endstage heart failure patients and the total collagen content during VAD support did not drop. This suggests that the down-regulation of other collagen types like collagen XV, as recently reported for 6 VAD patients [30], has a minor impact for the reversal of remodelling in CHF.

TGF beta1 is the main stimulus for Col1 transcription in the myocardium [10,11,29,31-33]. However, in patients, who were supported by VAD, the increased levels of TGF beta1 mRNA were not down-regulated by mechanical unloading. TGF beta1 activity is regulated by cleavage, secretion and binding to other peptides in the extracellular matrix. It is likely that elevated levels of Col1A1 mRNA reflect increased TGF beta1 activity, although this was not actually measured. The induction of extracellular matrix proteins by TGF beta1 is dependent on angiotensin II [34] and this may account for the observation that ACE-I and AT1-blockers inhibit or reverse the development of myocardial fibrosis in less severe heart failure [35,36]. We found that use of ACE-I in endstage heart failure patients during VAD support was associated with reduced expression of Col1A1 mRNA but not pre-formed total-collagen.

Cardiac fibroblast are the main source of myocardial collagen in CHF [28]. Mechanical strain has been shown in vitro to induce the transcription of Col1A1 in cardiac fibroblasts [29,37,38] due to a paracrine action of TGF beta1 [10,11]. Surprisingly, we found that the reduction of mechanical stress by VAD support on the human endstage heart failure ventricle has little effect on average Col1A1 gene expression. An increase in fibroblasts in the myocardium of patients with end-stage heart failure probably determines a constitutive high level of collagen synthesis which may be a required adaptation to contain left ventricular wall stress.

In conclusion, in patients with end-stage heart failure, remodelling of the extracellular matrix is not reversed by mechanical unloading with VADs alone. Use of ACE-I in addition to VAD has limited impact on myocardial fibrosis. Randomised controlled trials to investigate this phenomenon further are probably not feasible.


   Acknowledgements
 
The project was supported by grants of the Erich und Hanna Klessmann-Stiftung, Gütersloh/Westphalia, and the Förderverein Herzzentrum NRW, Bad Oeynhausen, Germany.


   References
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 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 

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