In a large systolic heart failure cohort derived from clinical practice, we found no meaningful associations between peripheral MMP-9 levels and baseline measures of ventricular remodeling or risk of adverse clinical outcomes. These results are in direct contrast to those for BNP, which showed strong cross-sectional associations with two different measures of cardiac remodeling and strong associations with risk of adverse outcomes. Our study thus does not support the use of peripheral MMP-9 level as a clinically useful biomarker in chronic systolic heart failure.
These findings contrast with previous reports that suggest a potential role of MMP-9 as a biomarker of cardiac remodeling and heart failure. These differences are largely attributable to differences in the populations under study. For example, Ahmed et al. detected elevated peripheral MMP-9 levels in patients with hypertension and concentric cardiac remodeling compared to normal controls (10
). Sundstrom et al. evaluated MMP-9 levels in a healthy population of 699 subjects free of clinical heart failure and previous myocardial infarction (6
). They found that, although levels were undetectable in the majority of subjects, there was a cross-sectional association between detectable MMP-9 levels, LV wall thickness, and LV dimensions in men but not in women. These studies suggest that MMP-9 may be a marker for early cardiac remodeling in selected patient populations such as those with hypertensive heart disease or other cardiovascular risk factors prior to the development of clinical heart failure.
More recently, Yan et al.
tested the association between plasma MMP-9 and ventricular volumes in 183 patients with systolic heart failure and demonstrated statistically significant correlations with ejection fraction and left ventricular volumes (7
). Although their sample size was relatively small, the authors’ ability to detect an association was strengthened by the use of a more homogenous clinical trial population and by the use of quantitatively measured ventricular volumes assessed over time. However, our results indicate that such associations do not necessarily translate into clinically meaningful associations in a less homogenous cohort that is more typical of clinical practice. In addition, Yan et al did not adjust for circulating BNP which, based on our analysis, might overshadow the observed associations with MMP-9. Hence, there may an association between MMP-9 and measures of cardiac remodeling in select circumstances, but our study casts doubt on the clinical utility of that association, especially given the inability of MMP-9 to predict clinical outcomes ( and ).
From a mechanistic standpoint, our findings are also consistent with the basic biology of natriuretic peptides and the MMP/TIMP systems. As demonstrated in numerous animal and human studies (reviewed in (2
)), BNP is specifically expressed by cardiac myocytes during cardiogenesis and is re-induced and released under conditions of mechanical stress and cardiac hypertrophy. Because of its cardiac specificity, BNP levels in the periphery show strong associations with both remodeling and heart failure. By contrast, MMPs are involved in extracellular matrix turnover in a variety of homeostatic and pathologic settings unrelated to cardiac remodeling, including wound healing (11
), cancer growth and metastasis (12
), inflammation (13
), and atherogenesis (14
). Given the limited specificity of MMP-9, it is not surprising that peripheral MMP-9 levels show inferior associations with ventricular remodeling and heart failure when compared to peripheral BNP.
Although our study does not support the use of circulating MMP-9 as a biomarker, we cannot exclude a causal role for myocardial MMPs and TIMPs in the pathogenesis of remodeling. We did not study MMPs within the myocardium directly, nor did we alter MMP function via the use of pharmacologic agents. Such experiments have been conducted in animal models and do suggest a pathogenic role for MMPs. For example, activation of MMPs via genetic deletion of TIMP-3 causes dilated cardiomyopathy in mice (15
), whereas inhibition of MMPs using transgenic (16
) and pharmacological approaches (17
) attenuates ventricular remodeling. The only published clinical trial of MMP inhibition to attenuate remodeling in humans showed no effect vs. placebo, but the agent used inhibited MMPs broadly and was limited by musculoskeletal toxicity (22
). Thus, the role of MMPs and TIMPs as mediators of remodeling in human heart failure or as therapeutic targets remains uncertain.
Several limitations warrant mention. First, we measured MMP levels and not MMP activity. Since MMP activity within the myocardium is probably a better predictor of matrix remodeling, one could argue that circulating MMP activity might be a superior biomarker than MMP level. However, circulating MMP activity would undoubtedly be influenced by circulating TIMPs and by MMPs released from extra-cardiac sources. Second, we did not analyze longitudinal changes in MMP-9 levels over time, and we cannot draw conclusions regarding temporal changes in cardiac structure or its relation to MMP-9. Third, we limited the echocardiographic parameters studied to the clinically used measures of ejection fraction and left ventricular dimensions. As shown by Yan et al.
), it is possible that MMP-9 levels associate with other echocardiographic parameters, such as quantitatively assessed ventricular volumes or measures of diastolic function. However, based on our findings, we can safely conclude that these associations would be smaller in magnitude that those for BNP. Finally, it is possible that use of previously frozen plasma or diurnal variation in MMP-9 level could introduce variability into our data that might mask associations of interest, although studies in normal subjects done by Tayebjee et al
indicate that diurnal variation is unlikely (23
In conclusion, our findings do not support the use of circulating MMP-9 levels as a clinical biomarker in systolic heart failure and verify the prognostic value of BNP in clinical practice. Further research in diverse patient populations is needed to clarify the utility of MMPs and other biomarkers of remodeling and heart failure. Moreover, further defining the mechanistic role of MMPs in human heart failure will require trials of specific MMP inhibitors or techniques that allow in vivo measurement of MMPs within the myocardium in human subjects.