Inflammation Research

, Volume 63, Issue 5, pp 329–334 | Cite as

The effect of prolonged systemic doxycycline therapy on serum tissue degrading proteinases in coronary bypass patients: a randomized, double-masked, placebo-controlled clinical trial

  • Immi Kormi
  • Hatem Alfakry
  • Taina Tervahartiala
  • Pirkko J. Pussinen
  • Juha Sinisalo
  • Timo Sorsa
Original Research Paper

Abstract

Objective

Serum matrix metalloproteinases (MMP-8, MMP-7) and their regulators may be associated with the risk of incident cardiovascular disease events. Doxycycline can be used as matrix metalloproteinase (MMP) inhibitor independent of its antimicrobial activity. We aimed to investigate serum inflammatory biomarkers during 4 months of doxycycline therapy in coronary bypass patients.

Materials and methods

Thirty-one non-smoking men who had previous coronary bypass surgery were randomly assigned to receive placebo or 100 mg doxycycline daily for 4 months. Serum samples were collected at baseline before the treatment, and at 2, 4, and 10 months. Serum levels of MMP-7, tissue inhibitor of matrix metalloproteinase (TIMP)-1, myeloperoxidase, and neutrophil elastase were analyzed with enzyme-linked immunosorbent assay, MMP-8 by immunofluorometric assay, and C-reactive protein by rate nephelometry.

Results

At baseline, no significant differences existed between the two groups. Serum levels of MMP-8, MMP-7, and MMP-8/TIMP-1 were and remained lower (p = 0.034, p = 0.041, and NS) in the doxycycline group relative to the placebo group at 4 months of follow-up.

Conclusions

Doxycycline decreases the systemic inflammatory burden in patients with myocardial infarction and especially down-regulates MMP-7, MMP-8, and MMP-8/TIMP-1. Doxycycline might prevent or reduce the risk of secondary myocardial infarctions by providing a systemic anti-proteolytic and -inflammatory shield.

Keywords

Atherosclerosis Matrix metalloproteinases Coronary bypass surgery Inflammation Doxycycline 

Introduction

Matrix metalloproteinases (MMPs) can be derived from various cellular sources but MMPs associated with cardiovascular pathologies are mainly produced by inflammatory cells. MMPs form a group of structurally related but genetically distinct zinc-containing endopeptidases that proteolytically degrade almost all extracellular matrix (ECM) and basement membrane components. They can also process various non-matrix bioactive substrates such as cytokines, chemokines, growth factors, and cell signalling molecules, thereby modifying immune response [1]. The proteolytic processing of ECM is important to facilitate the leukocyte migration into the intimal area [2], and has been implicated to contribute to atherosclerotic plaque rupture [3, 4] and subsequent acute coronary syndrome (ACS) [5]. The activity of MMPs is regulated by their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). TIMPs inhibit MMPs by forming enzyme-inhibitor complexes. Thus, the balance between MMPs and TIMPs is critical in the development and progression of atherosclerosis and is regarded to mirror proteolytic burden [1, 6, 7].

MMP-8, also known as collagenase 2, is capable to breakdown collagen type I, which is the major load-bearing molecule of the fibrous cap, a characteristic of the vulnerable, rupture-prone atherosclerotic plaque [8, 9, 10, 11]. MMP-8, matrilysin-1 (MMP-7), myeloperoxidase (MPO), and polymorphonuclear (PMN)-elastase being expressed in atherosclerotic lesions are thought to play a crucial role in plaque rupture and associated with subsequent pathological cardiovascular events [12, 13, 14, 15, 16]. MMP-7 can degrade ECM components as well as can proteolytically activate latent MMP-8 and inactivate TIMP-1. In addition, MPO can oxidatively activate pro-MMP-7 and -8, and inactivate TIMP-1 [14, 17, 18, 19].

Prolonged 4-month doxycycline medication was supposed to be useful to eradicate Chlamydia pneumoniae in cardiovascular disease. Doxycycline medication may be useful in preventing coronary artery disease events probably due to its antimicrobial effects [20]. Prolonged doxycycline treatment is beneficial in, e.g., Chlamydia trachomatis arthritis [21]. Doxycycline, a common tetracycline-derived drug, has also attracted increasing interest as a MMP inhibitor independently of its antimicrobial properties [22]. Doxycycline can reduce inflammatory burden including MMP-8, MMP-8/TIMP-1 ratio, PMN-elastase, and MPO as well as increase TIMP-1 in chronic inflammatory conditions such as chronic periodontitis, cardiovascular diseases (CVD), and abdominal aortic aneurysm (AAA) [22, 23, 24, 25]. The objective of the present study was to assess the effects of prolonged doxycycline therapy on serum MMP-8, -7, TIMP-1, MPO, PMN-elastase, and C-reactive protein (CRP) regarded as biomarkers of tissue destruction and systemic inflammation, in coronary bypass patients in a placebo-controlled double-blind clinical trial.

Materials and methods

Patients

The study was a randomized, double-masked, placebo-controlled clinical trial. The population comprised 31 men, aged 58 ± 5 years presenting with angiographically verified coronary heart disease which was severe enough to have required coronary bypass surgery. The operation had been done 6 months–5 years earlier. The patients with diabetes or impaired glucose tolerance, smoking, heart failure, neoplasm, chronic infectious or inflammatory systemic disease, recent (6 weeks) infection with general symptoms or need of antimicrobial drugs, antacids, body mass index >32 or hypolipidemic medication, known hypersensitivity to doxycycline were excluded. The ethics committee of Helsinki University Central Hospital and the National Agency for Medicines approved the study, and all the participants gave their written informed consent.

Study design and data collection

The study was performed on an intention-to-treat basis. The original goal was to reduce the risk of secondary cardiovascular events by eradication of persistent C. pneumoniae infection [26]. The patients were randomly assigned to receive placebo or 100 mg doxycycline once daily for 4 months. Serum samples were taken before treatment, and 2, 4 and 10 months after.

Serum determinations

The MMP-8 concentrations in serum samples were carried out by a time-resolved immunofluorometric assay (IFMA, Medix Biochemica, Kauniainen, Finland) with the inter assay coefficient of variation (CV)% 7.3 % and detection limit of 0.08 μg/l. TIMP-1 (Amersham Biotrak, GE Healthcare, Buckinghamshire, UK), MMP-7 (R&D Systems), MPO (Immundiagnostik AG, Bensheim, Germany), and PMN-elastase ELISA (eBioScience, Vienna, Austria) concentrations were determined by ELISA and CRP by rate nephelometry with detection limit 1.0 mg/l. The CV% for TIMP-1, MMP-7, MPO, and PMN-elastase were 13.1, 4.4, 13.0, and 5.6 % and detection limits 1.25, 0.016, 1.6, and 1.9 ng/ml, respectively. All assays were performed according to the manufacturers’ protocol. For calculation of MMP-8/TIMP-1 molecular ratio, the concentrations were converted into moles using molecular weight of 65 kDa and 28 kDa g/mol, respectively as described earlier [9, 27].

Statistics

The significance of differences between the characteristics of the doxycycline group and the placebo group was tested by t test or Mann–Whitney test, while proportions were tested by Chi-square or Fisher’s exact test. The significance of the differences in the mean change from the baseline in the serum concentrations between the treatment and placebo groups were analyzed by Mann–Whitney test. The analyses were done using SPSS version 15.0.

Results

The patient characteristics in the beginning of the trial are given in Table 1. The only difference between the groups was seen in the triglyceride levels (p = 0.05).
Table 1

Characteristics of the patients at baseline

 

Placebo (n = 15)

Doxycycline (n = 16)

Age (years)

56.9 ± 5.2

58.9 ± 5.2

Cholesterol (mmol/l)

5.9 ± 0.9

5.8 ± 1.0

HDL cholesterol (mmol/l)

1.0 ± 0.17

1.0 ± 0.09

LDL cholesterol (mmol/l)

3.9 ± 0.7

4.2 ± 0.8

Triglycerides (mmol/l)*

2.3 ± 2.0

1.3 ± 0.5

Body mass index

26.8 ± 2.8

26.1 ± 2.9

Systolic blood pressure (mmHg)

134 ± 13

136 ± 15

Diastolic blood pressure (mmHg)

81 ± 9

77 ± 9

Values are presented as mean ± SD

HDL high density lipoprotein, LDL low density lipoprotein

p = 0.05

Figure 1a shows that serum levels of MMP-8 decreased obviously in the doxycycline group while they increased in the placebo group during the follow-up. The difference between the groups was statistically significant at 4 months (p = 0.034). Serum MMP-7 levels increased in both groups over 2 months but decreased after that. The serum level was significantly lower in the doxycycline group at 4 months (p = 0.041) (Fig. 1b). Conversely, serum levels of TIMP-1 were obviously higher in the doxycycline group compared to the placebo group at baseline, 4 and 10 months (Fig. 1c), but the results did not reach statistical significance. The placebo group subjects had higher MMP-8/TIMP-1 ratios than the doxycycline subjects during the whole follow-up period (Fig. 1d). At 4 months’ time point, even though not statistically significant, the MMP-8/TIMP-1 ratios were strongly elevated in the placebo group compared to the doxycycline group (data not shown).
Fig. 1

Serum levels of MMP-8 (a), MMP-7 (b), TIMP-1 (c), and MMP-8/TIMP-1 (d) were analysed at baseline before the treatment, and at 2, 4, and 10 months in 31 non-smoking men. Patients were randomly assigned to receive placebo (n = 15, blue line) or 100 mg doxycycline (n = 16, red line) per day for 4 months. *p < 0.05 for the difference. Data are presented as mean values and vertical bars are standard error of mean (SEM)

As revealed by Fig. 2a, serum MPO levels declined in both groups during the follow-up time. Also serum PMN-elastase clearly reduced in the doxycycline group compared to the placebo group over 10 months of follow-up (Fig. 2b). In contrast, at 2 and 4 months, serum CRP levels were higher in the doxycycline group compared to the placebo group. At the end of the follow-up, serum CRP levels dropped in the doxycycline subjects compared to the placebo subjects (Fig. 2c).
Fig. 2

Serum levels of MPO (a), PMN-elastase (b), and CRP (c) were analysed at baseline before the treatment, and at 2, 4, and 10 months in 31 non-smoking men who had previous coronary bypass surgery. Patients were randomly assigned to receive placebo (n = 15, blue line) or 100 mg doxycycline (n = 16, red line) per day for 4 months. *p < 0.05 for the difference. Data are presented as mean values and vertical bars are standard error of mean (SEM)

Discussion

Our 4-month randomized, double-masked, placebo-controlled clinical trial suggests that doxycycline may reduce the risk of secondary myocardial infarctions (MI) through effective inhibition of MMP-8 and -7. These MMPs have been found in atherosclerotic lesions and cooperatively have the potential to thin the protecting fibrous cap by degrading ECM components, thereby causing plaque destabilization, plaque rupture, thrombosis, and acute myocardial infarction. PMN-elastase (a marker of leucocyte activation) like MMPs plays an important role in matrix degradation and is associated with an increased risk of future cardiovascular events. MMP-7, PMN-elastase, and MPO can activate proMMP-8 and inactivate TIMP-1 [4, 28, 29, 30]. Our study indicated that doxycycline intervention had no effect on MPO, and CRP levels; however, PMN-elastase levels were suppressed and TIMP-1 levels were obviously higher during 4-months of doxycycline therapy.

MMP-8, also known as neutrophil collagenase or collagenase-2, in addition to vascular wall cells, including endothelial cells and smooth muscle cells (SMCs), can also be expressed by various inflammatory cells during their infiltration into atherosclerotic lesion. MMP-8 and MMP-7 secreted by macrophages/foam cells digest collagen type I, the major scaffolding molecule of the atherosclerotic plaque, render plaques prone to rupture [10, 14, 31]. MMP-8 and -7 are increased in cardiac arrest patients as compared with healthy control [32]. Van den Borne et al. [33] showed that MMP-8 levels increased in human rupture infarcts relative to control infarcts. Elevated serum MMP-8 concentrations were strongly associated with subclinical atherosclerosis and predicted death from cardiovascular causes in men [9]. High plasma MMP-8 levels have been associated with presence and severity of chronic artery disease (CAD) [34] and with carotid artery plaque progression [12]. Furthermore, recent studies suggesting that high plasma or serum MMP-8 levels may reflect coronary plaque instability in patients with unstable angina (UAP) or ACS [35, 36].

Doxycycline is a commonly used broad-spectrum antibiotic, and exerts anti-collagenolytic effects independently of their antimicrobial properties by inhibiting both MMP-8 activity and synthesis in rheumatoid arthritis [37]. Lauhio et al. [21] have shown that serum MMP-8 levels of patients with reactive arthritis reduced by a 2-month doxycycline treatment. Previous study has revealed that doxycycline therapy improves the proteolytic balance in AAA, through selectively down-regulating MMP-8 protein levels [23]. García et al. [38] suggested that MMP-7 is decreased by doxycycline treatment. In agreement with these previous studies, the present study showed that doxycycline therapy statistically significantly reduced serum MMP-8 levels and at a lesser effect inhibited MMP-7 levels, which may stabilize vulnerable atherosclerotic plaques and improve clinical outcomes [1, 2]. The present findings further suggest that doxycycline medication can also reduce MMP-7 and MMP-8 activation cascade.

MMPs have a crucial role in the balance between collagen synthesis and degradation as well as in the regulation of proinflammatory immune responses. Normally, the activity of MMPs is regulated by TIMPs and changes in this balance may result in diseases associated with uncontrolled degradation of the ECM, such as ACS. TIMP-1 is a specific endogenous MMP inhibitor which restricts ECM degradation by inhibiting MMPs, thereby preventing plaque rupture [6, 7]. Elevated MMP-8/TIMP-1 ratio was strongly associated ACS [9, 36, 39]. In the present study, doxycycline therapy may modify vascular pathology, by restoring/reducing the MMP/TIMP ratio.

The weaknesses of our study include, firstly, the limited number of participants with relatively low statistical power for sub-grouping, and secondly, some patients had coronary bypass operation 6 months and others 5 years earlier which might cause large variation. However, for all patients, the period from the coronary bypass operation was at least 6 months and accordingly their coronary heart disease was stable. Also, the acute phase response was cleared as reflected in their serum CRP concentrations. Regular dose doxycycline-medication is associated with risks including diarrhea as well as super––and fungal infections. In the present study, the patients did not report any serious side effects [26].

In summary, our study suggests that doxycycline provides a systemic anti-proteolytic and -inflammatory shield, and, therefore, might protect against cardiovascular attacks. Furthermore, doxycycline at low dose [that is subantimicrobial-dose doxycycline (SDD)] has recently been demonstrated to reduce serum MMP-8, -9 and MMP-8/TIMP-1 [40]. Systemic inhibition of MMP-8 and -7 as well as MMP-8/TIMP-1 might be expected to reduce the incidence of plaque rupture or progression and improve the atherosclerosis lesion stability. Doxycycline thus may provide an anti-proteolytic, -inflammatory and anti-oxidative shield against systemic inflammation in secondary myocardial infarctions. Point-of-care adjunctive diagnostic tools are under development for serum MMP/TIMP analysis [28]. Overall, our initial findings suggest to conduct a comprehensive clinical trial including cardiovascular endpoints to address the ability of doxycycline to prevent and affect the course of thromboembolic diseases and it’s monitoring by the studied serum proinflammatory and tissue destruction biomarkers.

Notes

Acknowledgments

This study was supported by grants from the Ministry of Higher Education/Libya, the Sigrid Juselius Foundation (for PJP), the Academy of Finland (#1130408 for TS), and the Helsinki University Central Hospital Foundation (EVO for TS).

Conflict of interest

No conflicts of interest.

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Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Immi Kormi
    • 1
    • 2
  • Hatem Alfakry
    • 2
  • Taina Tervahartiala
    • 2
  • Pirkko J. Pussinen
    • 2
  • Juha Sinisalo
    • 4
  • Timo Sorsa
    • 2
    • 3
  1. 1.Oral and Maxillofacial DepartmentOulu University HospitalOuluFinland
  2. 2.Institute of DentistryUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of Oral and Maxillofacial DiseasesHelsinki University Central HospitalHelsinkiFinland
  4. 4.Division of Cardiology, Department of MedicineHelsinki University Central HospitalHelsinkiFinland

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