Correlations between Serum Inflammation Factors and Left Ventricular Remodeling in Acute ST Segment Elevation Myocardial Infarction

There is increased recognition that inflammation plays a key role in the pathogenesis of atherosclerosis and its complications.1 Recently, attention has been focused on the potential role of circulating inflammatory markers as risk predictors to indentify patients who are more likely to suffer a clinical event. In patients with myocardial infarction, the progressive left ventricular (LV) dilation, that is, ventricular remodeling, is linked intimately to adverse prognosis. A simple plasma marker that can allow early risk stratification would benefit patients in need of intensive therapy. The cardiac extracellular matrix (ECM), the connective tissue scaffold on which cellular elements are arranged, plays a vital role in the maintenance of myocardial structure and function, particularly that of the LV. Physiological integrity of ECM structure is largely under the control of the matrix metalloproteinase (MMPs) family of endopeptidases, and a fine balance between MMPs and tissue inhibitors of MMPs (TIMPs) is essential for maintaining the integrity of the highly organized and dynamic matrix that provides structural support for myocytes and a medium for non-myocytes, proteins, and signaling molecules.2 Previous studies reported that the activation of MMPs that degrade the extracellular matrix has been linked to adverse LV remodeling post-myocardial infarction.3, 4 Interleukin-6 (IL-6) and soluble CD40 ligand (sCD40L) also have been shown to be predictors of adverse outcome in patients with coronary artery disease (CAD).5, 6 However, a limitation of the previous studies is that inflammation markers were measured only at a single time point, and changes during follow-up were not measured. In this study, the circulating serum levels of the inflammatory markers (IL-6, sCD40L, MMP-9 and TIMP-1) were determined and echocardiographic assessment was carried out in patients with acute ST-segment elevation myocardial infarction (STEMI) at admission and 3-year follow-up visit, and we then evaluated the changes of the above inflammatory markers levels during 3-years follow-up period and the correlations between the above inflammatory markers with LV structure and function post-myocardial infarction.

The main findings of this study are that the levels of serum IL-6, sCD40L and MMP-9 were steadily increased among control subjects, remote myocardial infarction and acute STEMI patients, that TIMP-1 was elevated, and MMP-9/TIMP-1 ratio decreased markedly in remote STEMI, that MMP-9 measured at admission showed a positive association with great LVEDD and LVEDV, and that TIMP-1 positively correlated with E/A ratio measured at subsequent follow-up period. The results suggest that elevated levels of IL-6, sCD40L, and MMP-9 and the imbalance of MMP-9/TIMP-1 system are involved in the process of plaque rupture, leading to the incidence of myocardial infarction, and that MMP-9/TIMP-1 may also be linked to the post-infarction remodeling of myocardium, probably leading to heart failure.

Acute coronary syndrome (ACS) is triggered by dysfunctional endothelial and atherosclerotic plaque instability. The stage of plaque instability is that pro-inflammatory cytokines and chemoattractants induce leukocyte chemoattraction to the endothelium, and together with other triggers such as the CD40L-CD40 co-stimulation system activate plaque monocytes (macrophages). The macrophages then produce MMPs that disintegrate extra-cellular plaque matrix, causing coronary plaque instability.7 IL-6 is a circulating cytokine known to be secreted from a number of different cells including activated macrophages and lymphocytes, which could stimulates hepatocytes to synthesize acute phase response proteins such as C-reactive protein and fibrinogen. The CD40L on T-cells binding to the CD40 receptor on macrophages is involved in the multiple stages of atherosclerosis and ACS, inducing macrophages to secrete tissue factor, up-regulating the expression of adhesion molecules, and activating secretion of MMPs. Previous study8, 9 have shown, in agreement with our results, that the concentration of IL-6 and sCD40L are significantly elevated from stable CAD to ACS, as compared to control, possibly supporting their role in plaque instability and rupture.

MMPs are a tightly regulated group of zinc-dependent peptidases that participate in matrix turnover in both normal and pathological conditions.10 In the present study, we studied one member from the family of gelatinases, such as MMP-9, which has been found highly expressed in the shoulder regions of advanced atherosclerotic lesions and contributes to plaque instability.11 The main endogenous MMPs inhibitors are TIMPs, and TIMP-1 inhibits most MMPs except for MMP-2. Under normal circumstances, the activeity of MMPs and TIMPs maintain a balance between connective tissue synthesis and degradation. When the balance is disturbed, the undesired tissue destruction or remodeling takes place. Previous studes12-15 have reported that patients with ACS exhibited significantly higher levels of MMP-9 and TIMP-1 than those with stable angina and normal control subjects, and the higher levels were related to the presence of plaque rupture in the culprit lesion. In our pervious study,16 we found that acute STEMI patients exhibited significantly higher level of MMP-9 and slightly elevated TIMP-1 as compared to control, therefore, the MMP-9/TIMP-1 ratio was remarkably increased, indicating that an imbalance between MMP-9 and TIMP-1 in the micro-environment of the vulnerability atherosclerotic plaques may be responsible at least in part for plaque disruption eventually leading to occurrence of cardiovascular events. In the present study, we failed to find any significant difference of the MMP-9 and TIMP-1 levels between acute STEMI patients and control due to a small sample size. However, we found that the levels of MMP-9 and the ratio of MMP-9/TIMP-1 were significantly higher in acute STEMI patients than those in remote STEMI, which also add weight to our previous findings.

MMPs and TIMPs participate not only in the process of atherogenesis and atherosclerotic plaque destabilization, they may also influence LV dilation and function impairment after myocardial infarction.17-20 In the present study, we found that MMP-9 measured at admission showed a positive association with great LVEDD and LVEDV at 3-year follow-up visit, which add the additional weight to the above-described notion. We also found that TIMP-1 was elevated remarkly in remote myocardial, and that TIMP-1 at admission positively correlated with E/A ratio measured in the subsequent follow-up period. Thus, we speculate that TIMP-1, following the activation of MMP-9, plays a protective role during the phase of LV remodeling and function impairment. Indeed, MMPs inhibition has been postulated as a potential therapeutic intervention in patients with acute myocardial infarction. Beneficial effects of selective MMP inhibition on regional myocardial geometry post-myocardial infarction were shown in experiment animal models.21 Miyazaki, et al.22 found that LV remodeling might be suppressed in association with MMP-9 suppression in acute myocardial infarction patients treated with percutaneous coronary intervention and regular dose or half-dose-combination of renin-angiotensin system inhibitors. However, the broad spectrum MMP inhibitor PG-116800 failed to attenuate adverse LV remodeling after myocardial infarction in prevention of myocardial infarction early remodeling trial.23 Therefore, selective MMP inhibition seems to be the better solution.

The limitations of our study should be considered. First, although significant, the associations between MMP-9, TIMP-1 and LV remodeling were relatively weak, which can not be entirely due to relatively small sample size, nevertheless, a larger population is needed to confirm our findings. Second, we should study the change of the inflammatory markers during the period between admission and discharge, and then select the highest levels in the acute state. Ideally, control group should be the patients with stable CAD and healthy subjects, so as to observe the defferent levels of the inflammatory markers, and elucidate the role of inflammation in the different phases of CAD. Third, the development of ventricular remodeling and function impairment after myocardial infarction are strongly affected by the infracted area and drug treatment during follow-up period, and these factors should not be excluded in the study.

In conclusion, the admission levels of serum MMP-9 and TIMP-1 closely correlated with left ventricular structure and function, which may be involved in the process of post-infarction remodeling of myocardium.