Available data indicate extensive inflammatory processes exacerbate structural changes and may accelerate the development of heart failure [20-22]. In particular, increased collagen synthesis in the myocardium, along with its impaired degradation in response to pressure and volume overload, leads to collagen accumulation within the heart, causing structural remodeling, myocardial stiffness, and fibrosis [23,24]. Indeed, biomarkers of myocardial inflammation and ECM remodeling, such as MMPs, have previously been shown to be important predictors of mortality [25].
Here we found serum MMP-2, MMP-3, and TIMP-2 levels were significantly negatively correlated with ejection fraction values in patients with myocarditis. Elevated MMP-2 activity may lead to abnormal vascular remodeling by increasing the migration of vascular wall smooth muscle cells into the intima, increasing fibrosis, and reducing the elastin content [6,26]. In addition, MMP-2 increases the activity, adhesion, and aggregation of platelets and thus contributes to thrombus formation [13]. Furthermore, in patients with myocardial infarction, a higher initial concentration of MMP-2 was associated with a larger infarct area and a reduced ejection fraction in an observation lasting over several months [27]. Therefore, our results showing elevated serum MMP-2 levels and reduced cardiac function confirm the relationship already observed in patients with myocardial infarction.
We also observed a negative correlation between eGFR and MMP-2 levels. A previous study showed higher MMP-2 levels were associated with episodes of cardiovascular disease in patients with type 1 diabetes observed for 12 years, and that baseline eGFR weakened the relationship between MMP-2 and cardiovascular disease [28]. Therefore, the eGFR may at least partially shape the relationship between MMPs and cardiovascular diseases. This hypothesis is supported by the observation that MMP-2 causes changes that are characteristic for tubular epithelial-to-mesenchymal transition (EMT) of the kidneys, leading to their increased fibrosis, which, in turn, leads to impaired renal function [29]. Alternatively, higher MMP-2 levels may result from reduced kidney function, although this is less likely as serum MMP-2 levels are only slightly dependent on renal clearance (the molecular weight of MMP-2 is higher than that of albumin).
In addition to the negative correlation between eGFR and MMP-2, we observed a negative correlation between eGFR and MMP-3. MMP-3 concentration was also previously shown to be associated with a decrease in eGFR; however, the relationship between MMP-3 and total mortality did not change significantly after adjustment to the decrease in eGFR [30]. These results indicate increased concentrations of MMP-2 and -3 probably only partially contribute to the decrease in eGFR, which correlates positively with cardiovascular disease and total mortality [30].
MMPs may be of particular concern in heart failure patients with concurrent chronic kidney disease (CKD). Indeed, Du et al. showed MMP-2 and MMP-9 levels increased over time in damaged tubules and lead to renal fibrosis, which is a typical phenomenon in progressive renal disease [31]. Other studies have shown MMP-2 plays a pathological role in interstitial renal fibrosis, probably by inducing EMT and macrophage infiltration [32]. In addition, Neal et al. showed increased MMP-2, MMP-9, and TIMP-1 activity in the aorta of patients with progressive kidney disease, and increased activity of MMP-2 in the serum [33]. Increased tissue activity of MMP-2, MMP-9, and TIMP-2 levels were also demonstrated in rats with CKD, with elevated TIMP-2 levels likely compensating for the increased MMP activity. There was also a strong relationship between MMP-3 levels and albuminuria in rats with CKD, presumably due to increased MMP-3-dependent proteolysis of type IV collagen [17]. Furthermore, parallel studies in patients with CKD showed increased MMP-2 activity in arterial blood samples of patients who underwent kidney transplantation accompanied by vascular calcification [29].
The Hsu T-W et al. study demonstrated that baseline MMP-2, -3 and -9 levels were the independent predictors for faster eGFR decline and subsequent kidney disease progression. Their statistical analysis showed also, that low basal eGFR and higher MMP-9 levels were the independent predictors of mortality in CAD patients [34].
In our study, patients with chronic kidney damage had higher levels of MMP-2 and TIMP-2, although they were not significantly different from those with healthy kidneys in terms of N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and LVEF. In addition, the correlation between MMP-2 and TIMP-2 levels in patients with chronic kidney damage did not differ significantly from those without, indicating the balance is maintained between the MMP and its inhibitor in those with kidney damage. Although such activation of MMP activity has already been observed in the cardiopulmonary setting and in severe inflammatory processes, our study is one of the first to show that chronic kidney damage in patients with myocarditis increases MMP activity. Therefore, inhibition of MMPs may be a useful therapeutic strategy in patients with myocarditis and concomitant CKD.
Limitations
There are several limitations to our study. First, plasma levels of MMP-2, -3, -9, and of TIMP-2 were only determined at baseline. Therefore, the changes in plasma levels over time, revealing more details about outcome measures, are not known. Second, we do not know to what extent plasma levels reflect the local pathological situation at the tissue level. Finally, we only assessed a few MMPs and only one of the four known TIMPs, so other MMPs and TIMPs may be involved in this pathogenic process.