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European Journal of Heart Failure 2008 10(12):1201-1207; doi:10.1016/j.ejheart.2008.09.010
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© 2008 European Society of Cardiology

Alterations in circulating activin A, GDF-15, TGF-β3 and MMP-2, -3, and -9 during one year of left ventricular reverse remodelling in patients operated for severe aortic stenosis

Johannes L. Bjørnstada,b,e, Nils O. Neverdala,b, Øystein A. Vengena,b, Cathrine Wold Knudsenc, Trygve Husebyec, John Pepperf, Mons Liea,b, Geir Christensenb,d,e and Theis Tønnessena,b,e,*

a Department of Cardiothoracic Surgery, Ullevål University Hospital Oslo, Norway
b Faculty of Medicine, University of Oslo Oslo, Norway
c Department of Cardiology, Ullevål University Hospital Oslo, Norway
d Institute for Experimental Medical Research, Ullevål University Hospital Oslo, Norway
e Center for Heart Failure Research, University of Oslo Oslo, Norway
f Department of Cardiac Surgery, The Royal Brompton Hospital London, UK

* Corresponding author. Department of Cardiothoracic Surgery, Ullevål University Hospital, Oslo, Norway. Tel./fax: +47 23015268. E-mail address: thto{at}uus.no (T. Tønnessen).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Patients with aortic stenosis (AS) develop left ventricular remodelling with cardiomyocyte hypertrophy and increased fibrosis. Following aortic valve replacement (AVR) reverse remodelling usually takes place.

Aims: To examine circulating levels of members of the transforming growth factor (TGF) superfamily and matrix metalloproteinases (MMP), known to have important effects on hypertrophy and extracellular matrix, in patients operated for AS.

Methods: Circulating levels of activin A, GDF-15, TGF-β3, MMP-2, -3, and -9 were measured in twenty-two patients undergoing AVR preoperatively, and 2 days, six months and 12 months postoperatively. Echocardiography and a six minute walking test evaluated reverse remodelling and physical performance.

Results: Activin A increased at six (1081.00±98.05 pg/ml, p<0.05) and twelve months (1263.09±141.43 pg/ml, p<0.05) compared to the preoperative value (855.00±76.30 pg/ml) and correlated negatively to physical performance. The preoperative value was also increased compared to controls (639.54±63.05 pg/ml, p<0.05). GDF-15, MMP-3 and -9 were all increased at two days postoperatively (p<0.05). MMP-3 correlated with left ventricular end diastolic dimension (p<0.05). MMP-2 did not change during the study period. TGF-β3 was only slightly reduced at six months postoperatively.

Conclusion: The observed alteration in circulating levels of members of the TGF-β superfamily and MMPs might play a role in the reverse remodelling process following AVR for AS.

Key Words: Myocardial remodelling • Aortic valve replacement • TGF-β • Growth factors • Activin A • GDF-15 • MMP

Received August 17, 2008; Accepted September 25, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Patients with severe aortic stenosis (AS) develop left ventricular hypertrophy as a result of pressure overload. If not treated by aortic valve replacement (AVR), the adverse remodelling process will progress to overt heart failure [1,2]. Myocardial remodelling is associated with hypertrophy of cardiomyocytes combined with structural changes of the extracellular matrix such as increased collagen synthesis and fibrosis. Following AVR, reverse remodelling usually takes place. Normal myocardial mass is usually achieved within eighteen months [3,4]. First there is normalization of cardiomyocyte hypertrophy, whereas modification of the extra-cellular matrix may take several years [5]. These processes may be regulated by different mediators such as growth factors, cytokines and matrix metalloproteinases (MMP). However, little is known regarding longitudinal alterations of potential mediators of remodelling and reverse remodelling associated with operation for AS.

The myocardium responds to stress by synthesizing various mediators and cytokines [6-8]. Pressure overload, as seen in AS, is likely to induce alterations in growth factors. The transforming growth factor beta superfamily is a family of mediators that has several important biological functions related to growth and extracellular matrix [9-11]. Activin A has previously been associated with myocardial remodelling [12,13]. Growth differentiation factor 15 (GDF-15) is a biomarker of cardiac disease [14,15] with cardioprotective [16] and antihypertrophic effects in mice [17]. Moreover, expression of transforming growth factor beta 3 (TGF-β3) has been induced by unloading hypertrophied rat hearts, suggesting that it is a candidate for active reverse remodelling [18]. The MMPs constitute a family of proteolytic enzymes involved in heart failure and cardiac remodelling. They exert a number of effects in the myocardium primarily linked to changes in extracellular matrix [19].

To obtain further insight into alterations of growth factors and mediators associated with myocardial remodelling and reverse remodelling, the aim of the present study was to examine circulating levels of activin A, GDF-15 and TGF-β3, as well as MMP-2, MMP-3 and MMP-9 before and after AVR for AS. Furthermore, we wanted to relate these levels to the reverse remodelling process.

Twenty-two patients were included in the study and circulating levels of the different mediators were measured preoperatively, immediately postoperatively and at six and twelve months after operation. Furthermore, echocardiographic evaluation was performed at the same time points. Estimation of New York Heart Association (NYHA) class and a six minute walking test were also performed preoperatively and at six and twelve months.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients and Protocol
Twenty-two patients with severe symptomatic aortic stenosis (mean aortic gradient>50 mmHg or aortic valve area<0.7 cm2) were prospectively included in this study at Ullevål University Hospital, Oslo, Norway. The patients were a subgroup of patients also included in the ASSERT multicenter trial [4] and received either a stented (Mosaic®, Medtronic, Inc., Minneapolis, Minnesota, USA) or a stentless valve (Freestyle®, Medtronic, Inc.). Postoperatively, after receiving a bioprosthesis, patients were routinely treated with salicylates and not warfarin in our department. No patients underwent additional valve surgery. However, eight patients received additional CABG surgery (see Tables 1-3GoGo for patient characteristics). Blood samples were drawn and echocardiographic measurements performed preoperatively, before discharge (normally at the second postoperative day) and at six and twelve months. NYHA class determination and a six minute walking test were performed by a cardiologist preoperatively and at six and twelve months. Twenty-four volunteers without a history of heart disease (age 68±2 years) served as controls for the analyses of blood samples. Informed written consent was obtained from each patient. The study protocol was approved by the local ethics committee and conforms with the Declaration of Helsinki.


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  		Table 1 Patient characteristics and preoperative data

 


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  		Table 2 Patient-medication (n=22)

 


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  		Table 3 Haemodynamic and functional data

 
2.2. Plasma and Serum Analyses
Blood was drawn from an antecubital vein into chilled, standard EDTA tubes (1 mg/ml blood) and kept on ice. Blood was centrifuged within 30 min and the plasma and serum fractions immediately frozen and kept at –70 °C until analyzed. Commercially available kits were used for analyzing plasma concentrations of activin A (Serotec, UK), GDF-15 (R&D, USA), TGF-β3 (R&D, USA) and serum concentrations of MMP-2, -3 and -9 (R&D, USA). The coefficient of variation was 7.9% for activin A, 3.7% for GDF-15, 3.9% for TGF-β3 and <7% for MMP-2, -3, and -9.

2.3. Echocardiography
All echocardiographic examinations were performed by the same person (a trained cardiologist) and recorded on videotapes. All recordings were analyzed at a core laboratory by an experienced echocardiographer blinded to patient details, and in accordance with the recommendation of the American Society of Echocardiography as previously described [4,6]. Left ventricular mass (LVM) was calculated from the M-mode registration of the left ventricle (LV) in parasternal long axis, using the Penn Convention formula. Peak aortic valve gradients were determined from peak aortic flow velocity by using continuous-wave Doppler. Indexed values were obtained by dividing by body surface area.

2.4. Statistical Analyses
Data are presented as means±standard error of the mean (SEM). Data were analyzed using SigmaStat, version 3.1 (Systat Software, Inc., San Jose, CA, USA). One way repeated measures ANOVA was used. For data that were not normally distributed, we used one way repeated measures ANOVA on ranks. Data not normally distributed were transformed by natural logarithm to fit a normal distribution when examining the relation between two continuous variables by linear regression. Multiple comparisons were corrected for by Dunn's test for non-parametric and the Holm-Sidak method for parametric tests. Mann-Whitney Rank Sum Test or t test was used for comparing two groups of variables. p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Patient Characteristics
Patient characteristics are presented in Tables 1-3GoGo. Left ventricular mass index (LVMI) and NYHA class improved significantly at six and twelve months postoperatively and walking distance at twelve months postoperatively. CRP increased transiently at two days postoperatively (203.4±13.1 mg/l), but was within normal values at six and twelve months. Mean creatinine values were unchanged throughout the follow-up period. All of the patients were still alive as of 31st of December 2007.

3.2. Activin A
Preoperatively, mean plasma activin A was 855.00±76.30 pg/ml (Fig. 1A) which was 33% higher than in healthy controls (639.54±63.05 pg/ml). Plasma activin A was 819.46±122.02 pg/ml at two days postoperatively. Interestingly, at six and twelve months postoperatively there was a 26% and a 48% increase in plasma activin A (1081.00±89.05 and 1263.09±141.43 pg/ml, respectively) compared to the preoperative value. At 12 months postoperatively, activin A correlated positively with CRP (R=0.467) and negatively with maximum postoperative CKMB (R=0.499).


Figure 01
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  		Fig. 1 A) Plasma activin A levels (pg/ml) in control persons (CONTROL), preoperatively (PREOP), two days postoperatively (2dPO), six months postoperatively (6mPO) and twelve months postoperatively (12mPO). Data are presented as means±SEM. (*p<0.05 vs PREOP). B) Plasma concentration of activin A (pg/ml) twelve months postoperatively according to NYHA class. Data are presented as means±SEM. (*p=0.001). C) Correlation between activin A (pg/ml) and six minute walking test (in meters) preoperatively. Dashed lines show 95% confidence and prediction intervals.

 
Although activin A did not correlate significantly to LVMI at any time-point, there was a tendency to a correlation between activin A and peak aortic gradient at twelve months postoperatively (R=0.338, p=0.124). In line with this finding, patients in NYHA class II had a tendency to higher plasma concentration of activin A compared to patients in NYHA class I at six months (1339.50±184.77 vs 933.29±70.78 pg/ml, p=0.094). This difference was highly significant after twelve months (1968.00±178.15 vs 934.13±115.62 pg/ml, p=0.001, Fig. 1B). Preoperative six minute walking test correlated negatively to preoperative activin A (Fig. 1C), a finding which further supports that increased activin A is associated with decreased physical fitness. It should be noted that all patients were in either NYHA class I or II at six and twelve months.

3.3. GDF-15
Preoperatively, mean plasma GDF-15 was 385.76±49.79 pg/ml (Fig. 2, panel A) which did not differ significantly from healthy controls (337.98±19.08 pg/ml). Plasma GDF-15 was increased by 91% at two days postoperatively (735.10±96.33 pg/ml). At six and twelve months postoperatively plasma GDF-15 declined to preoperative values (333.18±42.93 and 398.31±52.37 pg/ml, respectively). GDF-15 at two days postoperatively correlated to maximum postoperative CKMB (Fig. 2, panel B). Moreover, GDF-15 correlated significantly to peak aortic gradient at six months postoperatively (Fig. 2, panel C), but did not reach statistical significance at twelve months. GDF-15 did not correlate to LVMI at any time-point throughout the observation period.


Figure 02
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  		Fig. 2 A) Plasma GDF-15 levels (pg/ml) in control persons (CONTROL), preoperatively (PREOP), two days postoperatively (2dPO), six months postoperatively (6mPO) and twelve months postoperatively (12mPO). Data are presented as means±SEM. (*p<0.05 vs PREOP). B) Correlation between plasma GDF-15 at two days postoperatively and natural logarithm of the maximum postoperative CKMB (µg/l). C) Correlation between plasma GDF-15 and peak aortic gradient (mmHg) at six months postoperatively. Dashed lines show 95% confidence and prediction intervals.

 
3.4. TGF-β3
Preoperatively, mean plasma TGF-β3 was 1075.70±17.29 pg/ml. Plasma TGF-β3 was slightly reduced at six months to 1015.41±38.34 pg/ml (p<0.05). However, at two days and twelve months postoperatively, plasma TGF-β3 did not differ from the preoperative value (1031.07±34.62 pg/ml and 1116.05±14.87 pg/ml, respectively).

3.5. Matrix Metalloproteinases
There were no significant alterations in serum MMP-2 levels throughout the study period (Fig. 3, panel A). In contrast, there was a significant increase both in MMP-3 and MMP-9 two days postoperatively (Fig. 3, panels B and C). MMP-3 increased from 16±2 ng/ml to 21±3 ng/ml at two days postoperatively. At six and twelve months MMP-3 serum levels were 18±3 and 19±3 ng/ml, respectively. Preoperatively, and at two days postoperatively, there was a significant positive correlation between MMP-3 and GDF-15 (R=0.425 and R=0.427, respectively). MMP-3 correlated with left ventricular end diastolic dimension (LVEDD) at 6 and 12 months postoperatively, although significance was not reached at 2 days postoperatively (Fig. 4).


Figure 03
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  		Fig. 3 Serum levels (ng/ml) of MMP-2, -3 and -9 preoperatively (PREOP), two days postoperatively (2dPO), six months postoperatively (6mPO) and twelve months postoperatively (12mPO). Data are presented as means±SEM. (*p<0.05 vs PREOP).

 


Figure 04
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  		Fig. 4 Correlation between ln MMP-3 and left ventricular end diastolic diameter (LVEDD in cm) six months postoperatively (6mPO) and twelve months postoperatively (12mPO). Dashed lines show 95% confidence and prediction intervals.

 
MMP-9 showed an even larger increase than MMP-3, from 160±12 ng/ml preoperatively to 269±37 ng/ml at two days postoperatively. At six and twelve months, serum MMP-9 levels were 163±20 and 167±16 ng/ml, respectively.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In the present study we have shown that circulating levels of members of the TGF-β superfamily and MMPs are altered differently in patients undergoing AVR for AS. Most strikingly, activin A is increased preoperatively compared to controls and continues to increase during the first year after operation. Moreover, at two days postoperatively, plasma concentration of GDF-15 and serum concentration of MMP-3 and MMP-9 were increased. We revealed a positive correlation between MMP-3 and LVEDD and between GDF-15 and MMP-3. These clearly differentially regulated mediators known to be involved in myocardial remodelling [12,13,17,19,20] are interesting, seen in the light of the pathophysiological changes taking place in the myocardium after AVR for AS. Six to eighteen months after AVR it is generally believed that there is mainly a reduction of hypertrophy of cardiomyocytes [5] a phenomenon which fits well with our observation of almost normal LVMI twelve months postoperatively. Interestingly, the reverse remodelling of myocardial fibrosis might take several years after relief of pressure overload [5]. However, the significant increase in MMP-3 and MMP-9 already at two days postoperatively might indicate that reverse remodelling of the extracellular matrix is initiated early after AVR.

Although plasma concentration of activin A was increased preoperatively compared to control there was a significant further increase at six and twelve months. Little is known about cardiac effects of activin A. However, it has been associated with myocardial remodelling in heart failure [12]. Activin A has been demonstrated to inhibit organization of sarcomeric proteins in cardiomyocytes induced by leukaemia inhibitory factor (LIF) [13]. LIF induces hypertrophy of cardiomyocytes via the gp130 receptor [21,22] and activin A has a negative effect on this growth response [13]. Thus, activin A might, at least in part, counteract the effect of certain remodelling stimuli on cardiomyocytes.

Reverse remodelling of fibrosis following AVR for AS takes years [5]. Activin A has been reported to play an active role in inducing fibrosis in lung [23,24], liver [25,26] and pancreas [27]. Thus, increased activin A might remain a profibrotic stimulus in the reverse remodelling phase after relief of pressure overload. At six and twelve months postoperatively, patients with a higher NYHA class (NYHA class II) had higher plasma concentration of activin A (compared to patients in NYHA class I). Moreover, preoperatively, activin A correlated negatively to the six minute walking test. These findings show that activin A is associated with reduced physical performance. Whether activin A is causally involved or just an epi-phenomenon remains to be shown.

Plasma concentration of GDF-15 was dramatically increased two days after AVR for AS. The significance of this finding is intriguing. In 27 628 apparently healthy American women aged 45 years and older, raised plasma concentrations of GDF-15 indicated an increased risk of developing future cardiovascular events [14]. GDF-15 has also been identified as a reliable biomarker for the risk of death in patients with non-ST-elevation acute coronary syndrome [15]. In the present study GDF-15 at two days postoperatively correlated positively to another marker of myocardial damage, maximal postoperative CKMB. Thus, GDF-15 might be a biomarker of the degree of myocardial damage after valve replacement. Whether GDF-15 is also involved in deleterious pathogenic processes in the heart is not clear from the previous clinical studies.

On the other hand, experimental studies have clearly shown that GDF-15 has cardioprotective [16] and antihypertrophic effects in mice [17]. The positive correlation between GDF-15 and MMP-3 at two days postoperatively might suggest that alterations both in myocardial hypertrophy (GDF-15) and extracellular matrix (MMP-3) are initiated early after AVR.

Plasma concentration of TGF-β3 was, although significantly, only minimally reduced at six months postoperatively. This subtle reduction is not likely to be of clinical relevance although the limited number of patients in the present study does not entirely preclude that there might be a causal relationship between TGF-β3 and reverse remodelling.

MMP-3 and MMP-9 were increased at 2 days postoperatively. These MMPs have previously been strongly associated with the myocardial remodelling process [19,20,28]. The increase in MMP-3 and MMP-9 as early as 2 days postoperatively might indicate increased collagen turnover and that reverse remodelling of the extracellular matrix after AVR for AS starts earlier than generally believed. MMP-3 has previously been associated with dilatation of the left ventricle [29] and this makes the positive correlation between MMP-3 and LVEDD in the present study especially interesting. In a recent study, Kelly and coworkers suggested that MMP-3 might be linked to myocardial remodelling and increased left ventricular volumes following acute myocardial infarction [28]. Thus, MMP-3 might also play a role in the reverse remodelling process in the present study.

In conclusion, we have observed an increase in plasma activin A in patients with AS compared to controls. There was a further increase in activin A at six and twelve months after AVR with higher levels in symptomatic patients. GDF-15, MMP-3 and MMP-9 were increased two days after AVR for AS. It is of particular interest that GDF-15 correlated to MMP-3 since the latter also correlated to LVEDD. These mediators might, thus, play a role in the reverse remodelling process given their known effects on fibrosis and cardiomyocyte remodelling, although no causal relationship has been demonstrated in the present study. Further studies are needed to reveal the exact role for each mediator in the reverse remodelling process following AVR for AS.


   Acknowledgements
 
The authors are grateful to the staff at the Dept. of Cardiothoracic Surgery and Dept. of Cardiology at Ullevål University Hospital, Oslo, Norway and Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London, UK. We want to thank Hilde Dishington for skilful technical assistance.

The study was supported by research grants from Medtronic, Inc., the Ingegerd and Viking Olov Bjørk Scholarship received by Professor Theis Tønnessen, the Rakel and Otto Kr. Bruun's Fund, the Family Blix Fund and the Eastern Norway Regional Health Authority.


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

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