Serum insulin-like growth factor-axis and matrix metalloproteinases in patients with rheumatic arthritis or rheumatic heart disease

Clinica Chimica Acta 367 (2006) 62 – 68 www.elsevier.com/locate/clinchim

Serum insulin-like growth factor-axis and matrix metalloproteinases in patients with rheumatic arthritis or rheumatic heart disease Shin-Da Lee a, Li-Mien Chen b, Wei-Wen Kuo c, Win-Tom Shu b, Wu-Hsien Kuo d, Erh-Jung Huang e, Chin-Chuan Tsai f, Ping-Chun Li g, Jer-Yuh Liu h, Ter-Hsin Chen i,1, Chih-Yang Huang h,*,1 a

School of Physical Therapy, Chung-Shan Medical University, Taichung, Taiwan Division of Medical Technology, Armed-Force Taichung General Hospital, Taichung, Taiwan c Department of Biological Science and Technology, China Medical College, Taichung, Taiwan d Division of Gastroenterology, Armed-Force Taichung General Hospital, Taichung, Taiwan e Center of General Education, Chung Tai Institute of Health Science & Technology, Taichung 406, Taiwan f School of Post Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan g Division of Cardiovascular Surgery, China Medical University, Taichung, Taiwan Institute of Biochemistry, Chung-Shan Medical University, No. 110, Section 1, Chien Kuo N. Rd., Taichung 40203, Taiwan, R.O.C. i Graduate Institute of Veterinary Public Health, National Chung-Hsing University, Taichung, Taiwan b

h

Received 1 October 2005; received in revised form 17 November 2005; accepted 18 November 2005 Available online 9 January 2006

Abstract Background: Insulin-like growth factor (IGF)-I plays an important role for maintaining cardiac functions. We clarified the unknown role of IGF-axis in rheumatic heart disease (RHD). Method: Interleukin (IL)-10, growth hormone (GH), IGF, IGF binding protein (IGFBP)-3 and matrix metalloproteinase (MMP) were measured by ELISA and zymography in 30 age range-matched normal subjects (control), 36 patients with acute phase of rheumatoid arthritis (RA) with positive rheumatoid factor (RF) and C-reactive protein (CRP), and in 43 patients with RHD with negative RF and CRP. Result: Compared with normal subjects, increased IL-10 level and decreased GH were found in RA group whereas unchanged IL-10 and decreased GH were found in RHD group. Compared with age range-matched normal subjects, decreased IGFBP-3, MMP-9 levels, unchanged IGF-I were found in RA group whereas decreased IGF-I levels, unchanged IGFBP3 and increased MMP-9 at age >30 years were found in RHD group. IGF-II was not changed in RA and RHD groups. Conclusion: These findings may imply that during inflammatory phase, the levels of anti-inflammation was high and total IGF-I and IGF bioavailability were maintained in patients with RA. Our findings in RHD may speculate that the long-term reduction of GH and IGF-I as well as the compensating effects of upregulated MMP-9 activity may be partially involved in the long-term pathogenesis from RHD to heart failure. Decreased GH, decreased IGF-I and increased MMP-9 activities may be possible diagnostic markers in RHD for developing heart failure. D 2005 Elsevier B.V. All rights reserved. Keywords: Endocrine system; GH-IGF-axis; MMPs; Rheumatic heart disease

1. Introduction

* Corresponding author. Tel.: +886 4 24730022x11682; fax: +886 4 23248195. E-mail address: [email protected] (C.-Y. Huang). 1 These authors contributed equally to the article. 0009-8981/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2005.11.015

Rheumatic fever is due to a pathological autoimmune reaction triggered after the upper respiratory tract infection with Streptococcus pathogens [1]. The autoimmune response of rheumatic fever directly affected the joints, heart, subcutaneous tissue, and central nervous system [1– 3].

S.-D. Lee et al. / Clinica Chimica Acta 367 (2006) 62 – 68

Rheumatic heart disease (RHD) is the most serious complication of rheumatic fever [2,4]. With chronic RHD, patients develop valvular lesions and/or cardiac abnormalities, such as valve stenosis with varying degrees of regurgitation, atrial dilation, arrhythmias, and ventricular dysfunctions [3,5]. Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease of undetermined etiology involving primarily the synovial membranes and the articular structures of multiple joints [6,7]. The erosion and destruction of synovial membranes often progressively result in pain, stiffness and swelling of joints and further lead to joint deformities [6]. Joint damage occurs in the early course of RA and 60% of patients have radiographic evidence of bony erosions at the time of diagnosis by 2 years [8]. Unfortunately, because bony erosions and deformities are largely irreversible, early diagnosis and early treatment, although challenging, are critical [7]. RA is a common systemic inflammatory arthropathy characterized by chronic synovitis and progressive joint destruction. Interleukin (IL)-10, a major immunoregulatory cytokine, was considered to mediate potent down-regulation of the pro-inflammatory response in RA, such as down-regulating TNF and IL-1 [9]. Higher IL-10 levels were found in circulation and synovial tissues from the patients with rheumatoid arthritis [10,11]. Plasma levels of IL-10 in patients with chronic heart failure were significantly higher than those observed in the normal health subjects [12]. However, the role of IL-10 in patients with chronic RHD, to our knowledge, is unknown. Growth hormone (GH), insulin-like growth factors I and II (IGF-I and -II) in the cardiovascular system appear to be powerful regulatory agents for maintaining cardiac function [13 –15]. IGF-I plays a specific role in the intricate cascade of events of cardiovascular function, such as promoting cardiac growth, improving cardiac contractility, cardiac output, stroke volume, and ejection fraction [13,16]. In humans, IGF-I appear to improve cardiac function after myocardial infarction by stimulating contractility and promoting tissue remodeling as well as low IGF-I levels were associated with an increased risk for myocardial infarction and heart failure [13,16,17]. The insulin-like growth factor binding protein-3 (IGFBP-3) is the most abundant binding protein carrying most of the circulating IGFs (90% in adult serum) and controls the actions of the IGFs by regulating their distribution and bioavailability to target tissues [18]. Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases capable of proteolytically degrading many of the components of the extracellular matrix and they have been identified as IGF-IGFBP complex degrading proteases [19]. However, the role of GH-IGF-IGFBP-axis and MMP in patients with chronic RHD, to our knowledge, has not been investigated. We investigated the possible role of GH-IGF-IGFBPaxis in chronic RHD and to clarify possible markers of

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pathogenesis of RHD for developing heart failure through evaluation of GH, IGF-I, IGF-II, IGFBP-3, IL-10, MMP-2 and MMP-9, compared with RA and normal health subjects.

2. Material and method 2.1. Subjects Rheumatic diagnoses were established by diagnosis of the attending rheumatologist and/or cardiologists by review of laboratory data, radiological analysis, clinic notes, and echocardiography. Thirty-six patients with rheumatic heart diseases (RHD) were selected by cardiologists according to clinical and echocardiography criteria and Jones’ modified criteria for a history of acute rheumatic fever [4]. Due to small number in <30 years RHD patients, 7 RHD patients were further recruited from advisement. In addition, 24 RA patients were classified and selected according to the American College of Rheumatology criteria [20] and 2 more specific inclusion criteria for acute phase of RA patients were positive rheumatoid factor (RF > 30 IU/ml) and positive C-reactive protein (CRP > 0.8 mg/dl). Due to small number in some age groups, 7 RA patients (< 30 years) and 5 RA patients (> 56 years) were further recruited from advisements. The exclusion criteria of patients were other known diseases, body mass index >27, hormonal replacement, pregnancy, lactation, and acute phase of rheumatic fever. Also, 30 age range-matched normal healthy subjects were recruited and completed in the current study. The protocol was approved by the institutional review board of the Armed-Force Taichung General Hospital, Taiwan, and the approved consent form was signed by each subject. 2.2. Blood sampling Overnight fasting blood samples were drawn from 7:00 to 9:00 a.m. by a trained phlebotomist via a venipuncture of an antecubital vein with the patient in the supine position. The blood samples were drawn and immediately used for Rate nephelometry. The other part of blood samples were separated by refrigerated centrifuge 3000 rpm for 15 min at 4 -C within 1 h of drawing and subsequently frozen at 80 -C until ELISA analysis and Gelatin zymography. 2.3. Rate nephelometry RF and CRP were measured by rate nephelometry. Rate nephelometry was performed on an Immage nephelometer (Beckman Instruments, Brea, CA) with Beckman reagents as described by the manufacturer’s technical brochure. Results were given as IU/ml for RF and mg/dl for CRP, and a result  30 IU/ml and 0.8 mg/dl was considered positive.

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S.-D. Lee et al. / Clinica Chimica Acta 367 (2006) 62 – 68

2.4. Enzyme-linked immunosorbent assay (ELISA) measurements IL-10, GH, IGF-I, IGF-II and IGFBP-3 levels were determined by commercially available ELISA kits (IL-10 ELISA kit; R&D Systems, Minneapolis MN; GH, IGF-I, IGF-II and IGFBP-3 ELISA kit; Diagnostic Systems Labs, Inc, Webster, TX) with the VERSA max tunable microplate reader (CA 94089, Molecular Devices, Sunnyvale, CA). Those assays are noncompetitive and marked with horseradish peroxidase-labeled detection antibody [21]. 2.5. Gelatin zymographyprotease assay The proteins extracts (20 Ag) from 16 AL sample were mixed thoroughly with a suitable volume of PBS buffer to 16 and 4 Al of dye. Gelatin zymography analysis was carried out by loading 20 Al of the extracts 0.1% gelatin and 8% SDS –PAGE and ran by electrophoresis at 140 V for 2.5 h. The gels were washed in a 2.5% Triton X-100 solution with shaking for 30 min and then incubated in 50 ml reaction buffer (40 mmol/l Tris – HCl, pH 8.0; 10 mmol/l CaCl2, 0.01% NaN3) at 37 -C for 12 h before staining with 0.25% Coomassie brilliant blue R-250 in 50% methanol and 10% acetic acid for 1 h. Quantitative analysis was preformed after discoloring the stain in a destaining solution (10% acetic acid, 20% methanol) twice for 30 min. The MMP-9 specific activities were quantified as mentioned above using a colorimetric assay which uses an artificial proenzyme containing a specific domain recognised by MMP-9.

with 3 age ranges (< 30 years, 31¨55 years, and >56 years) i.e., 43 patients with RHD (n = 10; 21, 12), 36 patients with RA (n = 10; 16, 10), and 30 normal healthy subjects (control group, n = 10, 10, 10). 2.7. Statistic analysis All parameters (IL-10, GH, IGF-I, IGF-II, IGFBP-3 and MMP-9 activity) were analyzed by an analysis of variance using the general linear model (GLM) in a one-way ANOVA with post-hoc comparison among age range-matched normal healthy subjects, patients with RA, and patients with RHD. In all cases, a difference at P < 0.05 was considered statistically significant. All data presented in the text, tables, and figures are means T SD.

3. Results 3.1. Interleukin-10 RF > 30 IU/ml and CRP > 0.8 mg/dl were found in patients with rheumatoid arthritis (RA) in all 3 age ranges whereas RF < 30 IU/ml and CRP < 0.8 mg/dl were found in patients with RHD (Table 1). Serum IL-10 was significantly ( p < 0.01) increased in patients with RA but IL-10 was unchanged in patients with RHD in all 3 age ranges i.e. < 30, 31¨55, >56 years, compared with normal health subjects (Con, control group) (Table 1, Fig. 1). 3.2. Growth hormone

2.6. Protocol To avoid degradation of IL-10, GH, IGF-I, IGF-II, IGFBP-3, and MMPs, all samples were defrosted before testing. Serum IL-10, GH, IGF-I, IGF-II, and IGFBP-3 levels and serum MMP-9 activity were measured by ELISA and gelatin zymography protease assay, respectively. All tests were performed by experienced technologists in a blinded design. All data were then divided into 3 groups

Compared with age range-matched normal subjects, decreased GH was found in RA and RHD group in all 3 age ranges i.e. < 30, 31¨55, > 56 years old (Table 1, Fig. 2). 3.3. IGF-I axis and MMP-9 Compared with age range-matched normal subjects, unchanged IGF-I with decreased IGFBP-3 levels were

Table 1 Age

Number of subject RF ( ) < 30 IU/ml CRP ( ) < 0.8 mg/dl IL-10 (pg/ml) MMP-9 GH (mg/ml) IGF-I (ng/ml) IGF-II (ng/ml) IGF-BP3 (ng/ml)

Control <30

31¨55

>56

10

10

10

Acute rheumatic arthritis (RA)

Chronic rheumatic heart disease (RHD)

<30

10 ++ ++ 7.4 T 0.6 7.8 T 0.8 9.4 T 0.5 23.4 T 2.1** 100.0 T 5.8 64.8 T 3.8 105.2 T 5.4 67.2 T 5.7* 5.81 T 0.64 4.32 T 0.43 4.88 T 0.33 0.78 T 0.09** 85.8 T 5.9 95.9 T 6.8 89.4 T 5.9 85.4 T 6.4 676.5 T 29.9 699.4 T 21.6 712.9 T 34.7 768.3 T 52.9 25.5 T 1.5 27.2 T 2.1 28.2 T 1.8 14.7 T 2.8**

31¨55

>56

<30

31¨55

>56

16 ++ ++ 24.1 T 2.2** 42.7 T 2.0** 0.50 T 0.08** 90.5 T 4.4 834.2 T 38.7 17.2 T 2.0**

10 ++ ++ 19.9 T 2.6** 26.9 T 1.6** 0.47 T 0.07** 88.6 T 6.3 744.6 T 32.2 14.1 T1.3**

10

21

12

7.13 T 0.88117.9 T 7.1. 2.13 T 0.36**,63.0 T 5.2**,653.6 T 34.7 25.8 T 2.3-

8.16 T 0.69160.0 T 9.5*,1.84 T 0.67**,56.7 T 5.5**,691.0 T 38.4 26.4 T 1.8-

6.88 T 0.72120.6 T 7.9*,1.54 T 0.27**,58.3 T 5.8**,672.4 T 32.2 20.6 T 1.8-

Values are means T SD. Definition of abbreviations: RF=rheumatoid factor; CRP=C-reactive protein; IL-10=interleukin-10; MMP-9=matrix metalloproteinase9; GH=growth hormone; IGF-I=insulin-like growth factor-I; IGF-II=insulin-like growth factor-II; IGFBP3=insulin-like growth factor binding protein 3. *p < 0.05. **p < 0.01. Significant difference between control and rheumatic arthritis or control and Rheumatic heart disease. .p < 0.05. -p < 0.01 Significant difference between rheumatic arthritis and rheumatic heart disease.

S.-D. Lee et al. / Clinica Chimica Acta 367 (2006) 62 – 68

##

**

20

(A)

10

##

40

0

RHD

Con

Fig. 1. Serum interleukin-10 (IL-10) measured in normal health subjects (Con, control group), patients with rheumatoid arthritis (RA), and patients with rheumatic heart disease (RHD) with 3 age ranges: <30 years (white; n = 10, 10, 10), 31¨55 years (gray) (n = 10, 16, 21), and >56 years (black) (n = 10, 10, 12). NS, no significant difference, **p < 0.01 significant different between RA and control group or RHD and control group, or ## p < 0.01 significant difference between RA and RHD in individual age group. Values represent mean T SD.

found in RA group in all 3 age ranges i.e. < 30, 31¨55, >56 years whereas decreased IGF-I levels with unchanged IGFBP-3 levels were found in RHD group. (Table 1 and Fig. 3). In subjects >30 years, MMP-9 activity was significantly ( p < 0.01) decreased in patients with RA, but MMP-9 activity was significantly ( p < 0.05) increased in patients with RHD, compared with normal health subjects (Table 1, Fig. 4). In < 30 years patients, mean MMP-9 activity was significantly ( p < 0.05) decreased in 10 patients with RA but MMP-9 activity was unchanged in the 10 patients with RHD, compared with ten normal health young subjects.

(B)

RA

40

RHD

NS ##

**

IGF-BP3 (ng/ml)

RA

NS

80

0 Con

0~30 31~55 >56

**

120

IGF-I (ng/ml)

IL-10 (pg/ml)

0~30 31~55 >56

NS

30

65

30 20 10 0 Con

RA

RHD

Fig. 3. Serum insulin-like growth factor (IGF)-I and insulin-like growth factor binding protein (IGFBP)-3 measured in normal health subjects (Con, control group), patients with rheumatoid arthritis (RA), and patients with rheumatic heart disease (RHD) with 3 age ranges: <30 years (white; n = 10, 10, 10), 31¨55 years (gray) (n = 10, 16, 21), and >56 years (black) (n = 10, 10, 12). NS, no significant difference, **p < 0.01 significant different between RA and control group or RHD and control group, or ##p < 0.01 significant difference between RA and RHD in individual age group. Values represent mean T SD.

with age range-matched normal health subjects (Table 1, Fig. 5).

3.4. IGF-II Serum IGF-II was not changed in patients with RA and in patients with RHD with all 3 age ranges, compared

8

##

** hGH (mg/ml)

0~30 31~55 >56

**

6

4

2

0

Con

RA

RHD

Fig. 2. Serum growth hormone (GH) measured in normal health subjects (Con, control group), patients with rheumatoid arthritis (RA), and patients with rheumatic heart disease (RHD) with 3 age ranges: <30 years (white; n = 10, 10, 10), 31¨55 years (gray) (n = 10, 16, 21), and >56 years (black) (n = 10, 10, 12). NS, no significant difference, **p < 0.01 significant different between RA and control group or RHD and control group, or ## p < 0.01 significant difference between RA and RHD in individual age group. Values represent mean T SD.

4. Discussion Our major findings can be summarized as follows: 1) Compared with age range-matched normal subjects, IL-10 level and decreased GH were found in RA group while unchanged IL-10 and decreased GH were found in RHD group. 2) Compared with age range-matched normal subjects, unchanged IGF-I with decreased IGFBP-3, MMP-9 levels were found in RA group whereas decreased IGF-I levels unchanged IGFBP3 levels and increased MMP9 were found in adult RHD group. 3) IGF-II was not changed in RA and RHD groups, compared with normal subjects. 4.1. IL-10 and GH-IGF-axis In the current experimental design, patients with RA herein were all co-existed with positive RF and positive CRP, which may imply that RA patients we selected were in an acute inflammatory status. Our goal was rather to distinguish the relative changes in IL-10 and GH-IGF-axis in chronic RHD, compared with normal

S.-D. Lee et al. / Clinica Chimica Acta 367 (2006) 62 – 68

(A)

M

Control

RA

4.2. RA

RHD

MMP-9

82 kDa

MMP-2

62 kDa

1

2

3

4

5

6

7

8

9

(B) 200

0~30 31~55 >56

##

MMP-9 (%)

** ##

150

#

*

100

* **

50

**

0 Con

RA

RHD

Fig. 4. (A) Represented activities of matrix metalloproteinase (MMP)-2 and MMP-9 were measured by gelatin zymography analysis in normal health subjects (Con, control group), patients with rheumatoid arthritis (RA), and patients with rheumatic heart disease (RHD) with 3 age ranges: <30 years (land 1, 4, 7), 31¨55 years (land 2, 5, 8), and >56 years (land 3, 6, 9). (B) Matrix metalloproteinase (MMP)-9 activity relative to that of <30 years control group measured in normal health subjects (Con, control group), patients with rheumatoid arthritis (RA), and patients with rheumatic heart disease (RHD) with 3 age ranges: <30 years (white; n = 10, 10, 10), 31¨55 years (gray) (n = 10, 16, 21), and >56 years (black) (n = 10, 10, 12). NS, no significant difference, *p < 0.05, **p < 0.01 significant different between RA and control group or RHD and control group, or ##p < 0.01 significant difference between RA and RHD in individual age group. Values represent mean T SD.

subjects and acute phase of RA patients without cardiac disorder. The GH-IGF-I axis plays an essential role in the cardiovascular system. Although the GH-IGF-I axis is a closely coordinated system, both GH and IGF-I have independent actions [15,22]. The IGFBP that carries most of the circulating IGF (90% in adult serum) is IGFBP-3, existing predominantly as a 150 kDa ternary complex (IGF1, IGFBP-3, and a bound acid-labile subunit) [18]. MMPs, a family of proteases, are involved in the degradation of extracellular matrix proteins and play a significant role in the development of cardiac remodeling. MMPs have been implicated in the degradation of IGFBPs as well as IGF-I becomes bioavailable for its receptors upon its dissociation from IGFBP through IGFBP degradation [19,23]. Furthermore, the anti-inflammatory cytokine IL-10 was shown to downregulate the production of MMPs [24]. Thereby, the equilibrium among MMPs, IGF-I and IGFBP-3 directly affects IGF bioavailability and the interaction between IL-10 and MMPs and between GH and IGF-I may indirectly affect IGF system.

Although the etiology of RA is still unknown, genetic, hormonal, viral, and inflammatory factors are suspected as initiator factors. IL-10, anti-inflammatory factor, is spontaneously produced in RA and is an important immunoregulatory component in the cytokine network of RA [25]. Our findings showed that increased IL-10 level in acute phase of RA group was not found in RHD group, suggesting that RA group in acute phase had higher anti-inflammatory cytokines such as IL-10 than chronic RHD patients and normal subjects. In consistent with one previous study, IL-10 measured by ELISA in the blood was significantly higher in forty-five RA patients than in 30 health subjects [26]. Another study suggested that the high IL-10 production found in patients with RA may be protective, especially against progression of joint destruction in RA [27]. In the current study, decreased GH, unchanged IGF-I with decreased IGFBP-3 and decreased MMP-9 levels were found in acute phase of RA. In consistent, symptomatic RA in previous study was observed with elevated serum GH without concomitant changes in IGF-I compared to individuals from the normal health subjects [28]. Similar or conflicting findings were reported in the previous studies [29,30], all of which did not distinguish acute phase of RA. These discrepancies might be caused in part by differences in gender of the patients, in the acute phase of the disease, and in habitual exercise. Since IL-10 will downregulate MMPs, in acute phase of RA, the decreased MMP-9 levels may be in part explained by inhibition of the increased IL10. Although MMP-9 levels were decreased, the unchanged IGF-I and decreased IGFBP-3 in RA patients may still be able to maintain IGF bioavailability to prevent heart damage. 4.3. RHD GH and IGF-I not only promote the growth and differentiation of the cardiac tissue [14,16] but also play a 0~30 31~55 >56

NS

1000 800

IGF-II (ng/ml)

66

600 400 200 0 Con

RA

RHD

Fig. 5. Serum insulin-like growth factor (IGF)-II measured in normal health subjects (Con, control group), patients with rheumatoid arthritis (RA), and patients with rheumatic heart disease (RHD) with 3 age ranges: <30 years (white; n = 10, 10, 10), 31¨55 years (gray) (n = 10, 16, 21), and >56 years (black) (n = 10, 10, 12). NS, no significant difference between two groups in individual age group. Values represent mean T SD.

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role in the regulation of immunity and inflammation [31]. GH and IGF-I activate several mechanisms that play a protective role against the development of heart failure, which protective include ventricular unloading, deactivation of neurohormonal components, antiapoptotic effect and enhanced vascular reactivity [32,33]. GH and IGF-I concentrations were suppressed in patients with chronic heart failure [34]. Our findings showed that unchanged IL10, increased MMP-9, decreased GH, and decreased IGF-I were found in RHD patients, strongly suggesting that altered GH-IGF-axis and IGF dysfunction occurred in RHD. However, no other relative studies about the role of GH and IGF-I axis in patients with RHD were previously presented. Exogenous administration of GH and subsequently increased production of IGF-I could modulate myocardial remodeling and improved pump function of left ventricular in patients with heart failure [35]. Herein, decreases in total IGF-I, without change in IGFBP-3 levels found in RHD patients implies that circulating total IGF-I and IGF-I bioavailability must be lower in RHD, which may contribute to heart diseases. In contrast, increased MMP-9 may not only potentially exert a compensatory role to enhance IGF-I bioavailability but also develop cardiac remodeling. 4.4. Further hypotheses for clinical application Our findings can provide a future hypothesis that the reduction of GH and IGF-I, and the increase of MMP-9 activity cannot only be used as the marker of diagnosing the developing heart failure in patients with RHD, but also provide an explanation of the pathogenesis from RHD to heart failure. For clinical application, further questions were raised whether growth hormone replacement and/or MMP9 inhibitor administration will minimize the abnormality of GH-IGF-axis or diminish the over-activity of MMP9 to prevent the development of heart failure from RHD. Of course, further clinical studies are needed to prove or against our hypotheses for clinical application.

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