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This editorial refers to "Prognostic impact of matrix metalloproteinase gene polymorphisms in patients with heart failure according to the aetiology of left ventricular systolic dysfunction"1 by Bauters et al. on page 688
An important structural milestone in patients with progressive heart failure is myocardial remodelling, although the inciting stimuli can be diverse. Pharmacological interventions targeted at altering this adverse left ventricular (LV) myocardial remodelling process hold therapeutic promise. However, designing an appropriate therapeutic regimen for interrupting the progression of myocardial remodelling requires an understanding of the basic molecular and cellular mechanisms that drive this process. Myocardial remodelling can be defined as the changes that occur within both the cellular and extracellular compartments and result in alterations in LV myocardial and chamber geometry. It is now well recognised that changes in the myocardial extracellular matrix contribute to the progressive remodelling process. Therefore, the identification and understanding of the biological systems that contribute to myocardial matrix remodelling hold particular relevance with respect to developing new diagnostic and therapeutic approaches for heart failure. Over the past several years, basic and clinical research has focused on the identification and understanding of the proteolytic systems that degrade the normal myocardial matrix during the progression and development of heart failure.
Matrix metalloproteinases (MMPs) and the heart failure process
The MMPs are a family of zinc-dependent proteases that degrade constituent components of the extracellular matrix and have been identified in normal and failing myocardium.13 The MMPs can be classified into subgroups based on substrate specificity and/or structure and include collagenases, such as MMP-1 and MMP-13, stromelysins, which include MMP-3, gelatinases, which include MMP-2 and MMP-9, and membrane-type MMPs (MT-MMPs). The stromelysins, such as MMP-3, are of particular interest since this enzyme subtype possesses a wide substrate portfolio and can activate other MMPs. The gelatinases, or MMP-2 and MMP-9, have been the most studied because these subtypes are amenable to a number of in vitro measurement approaches.1,2 In patients with end-stage cardiomyopathic disease, changes in a number of these MMP subtypes have been documented.2,3 Specifically, increased myocardial levels of MMP-3, MMP-2, and MMP-9 have been identified in patients with cardiomyopathic disease due to both ischaemic and nonischaemic aetiologies. In addition, circulating plasma levels of MMP-2 and MMP-9 have been reported in patients with cardiomyopathy and related to the severity of the disease process.4 In animal models of heart failure, a causeeffect relationship has been demonstrated through the use of MMP transgenic constructs as well as pharmacological MMP inhibition.1,2 Based on these past basic studies and clinical observational reports, a consensus is building that the induction and activation of myocardial MMPs contribute to adverse LV remodelling and thereby contribute to the progression of the heart failure process.
MMP transcriptional control and gene polymorphisms
Due to the potent proteolytic capacity of MMPs, the transcription of MMPs is under tight control.5,6 MMP mRNA expression can be influenced by a variety of chemical agents, neurohormones, corticosteroids, and cytokines. These bioactive molecules influence MMP gene expression through the formation of transcription factors that bind to specific response elements on MMP gene promoters. While the integration of these transcription factors is a highly complex process, what is clear is that the induction of MMPs is not a uniform process. For example, following myocardial infarction, certain MMP types are reduced in the myocardium, whereas a robust increase in other MMP types occurs.7 Moreover, this differential expression of MMP types following myocardial infarction is region- and time-dependent. Similarly, in patients with cardiomyopathic disease, certain MMP types are increased in ischaemic cardiomyopathy, but remain unchanged in nonischaemic cardiomyopathic disease.3 This is likely to be due to differences in the location, type, and number of transcription-factor binding sites located in each of the MMP gene promoter regions.
MMP gene polymorphisms have now been identified for several of the MMP subtypes.810 The polymorphisms that have been identified thus far often affect the promoter region of the MMP gene and thereby influence critical steps in the binding of transcription factors or the overall efficiency of transcription. The most intensely studied to date are polymorphisms that occur in the promoter region for MMP-3 and MMP-9. A naturally occurring variant in the MMP-3 promoter region is the 5A/6A allele which signifies a 5- or 6-adenine sequence, respectively. The 5A allele has been associated with increased MMP-3 promoter activity and, in turn, increased relative MMP-3 protein levels.8 In contrast, the 6A allele has been associated with reduced MMP-3 promoter activity. In patients homozygous for the 5A allele, a corresponding increase in MMP-3 tissue levels occurs, whereas in patients homozygous for the 6A allele, decreased MMP-3 tissue levels are observed.8 With respect to MMP-9, a gene variant has been observed in the promoter region located at position 1562 relative to the transcription start site. This MMP-9 variant is a single-base substitution where a transition between cytosine (C) and thymidine (T) occurs. The T allele results in a higher relative level of promoter activity when compared to the C allele, probably due to preferential binding of a repressor protein to the C-allele variant.10 While the molecular basis for the differences in MMP-9 promoter activity remain an area of investigation, a recent clinical study demonstrated that in patients with pre-existing cardiovascular disease, the presence of MMP-9 1562(T) allele resulted in increased plasma levels of MMP-9 protein.9 Moreover, increased plasma MMP-9 levels were associated with significantly reduced survival and a nearly twofold increase in the relative risk of cardiovascular-related death.9 Thus, there is emerging clinical evidence that MMP genetic polymorphisms can contribute to the relative levels of MMP protein and, in turn, influence cardiovascular outcomes.
In this issue, the study by Mizon-Gerad et al.11 examined the potential relationship between specific MMP gene polymorphisms and outcomes in patients presenting with pre-existing LV failure due to cardiomyopathy. In this study, over 400 patients were genotyped with respect to the MMP-3 polymorphism (5A/6A allele), MMP-9 polymorphism (1562T) allele), and also for the presence of an MMP-2 polymorphism (promoter amino acid substitution at 1306). This study is similar to a much larger clinical study of MMP gene polymorphisms and survival.9 However, one of the unique aspects of the study by Mizon-Gerad et al. is that the aetiology of the underlying cardiomyopathy was stratified as ischaemic or nonischaemic. This stratification is a logical and important consideration in light of the fact that past studies have identified differences in myocardial MMP levels in ischaemic versus nonischaemic cardiomyopathy.2,3 These investigators observed that homozygosity for the 5A allele in patients with nonischaemic cardiomyopathy was associated with poorer survival, and statistical modelling revealed that this MMP-3 polymorphism was an independent predictor of cardiac mortality, with a hazard ratio of 2.92. However, the relationship between the MMP-3 polymorphism was not observed in patients with ischaemic cardiomyopathy. The presence of the T nucleotide in the MMP-9 promoter region was an independent predictor of survival in all patients, irrespective of the underlying aetiology. This study failed to identify any significant relationships between the MMP-2 promoter polymorphism and cardiac mortality. This study continues to build upon an emerging body of evidence that MMP polymorphisms and, by extension, changes in MMP protein levels, contribute to the progression of the heart failure process. While these studies are exciting, there are some points that must be taken into account. First, in the study by Mizon-Gerad and collegues it remains unclear whether and to what degree the MMP polymorphisms manifest as a change in actual MMP levels in the myocardium. However, recent studies have identified a strong relationship between MMP-3 5A polymorphism and MMP-3 tissue levels and between MMP-9 T-allele polymorphism and circulating levels of MMP-9.8,9 Nevertheless, these MMP genotyping studies do not provide a clear causeeffect relationship between the MMP system and cardiac mortality in patients with pre-existing LV failure. Another consideration is that these MMP polymorphisms may not occur as independent events but rather be associated with other polymorphisms in the genome, such as cytokines and mediators of the inflammatory response. However, it is intriguing to speculate that these MMP polymorphisms may identify patients that may be more vulnerable to adverse myocardial remodelling and, therefore, to a more rapid progression of the heart failure process.
Since the first report by Gross et al.12 regarding the resorption of a tadpole tail, it is now clearly recognised that MMPs play a critical role in the pathological myocardial remodelling processes. Studies such as that presented by Mizon-Gerad and colleagues emphasise the importance of linking clinical outcomes research to fundamental aspects of MMP biology. It is through these studies that hypotheses are generated, translational studies initiated, and new diagnostic and therapeutic targets are identified with respect to the LV remodelling process, which potentially could improve outcome for millions of patients suffering from heart failure.
Footnotes
1 doi:10.1016/j.ehj.2004.01.015
References
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