Role of matrix metalloproteinases in mitral valve regurgitation: Association between the of MMP‐1, MMP‐9, TIMP‐1, and TIMP‐2 expression, degree of mitral valve insufficiency, and pathologic etiology

Abstract

Background The pathogenesis of mitral valve insufficiency is not yet fully understood. Several studies stressed the role of matrix metalloproteinases (MMPs) in the emergence of valvular pathologies. The primary objective of the present study is to analyze the role of selected MMPs and their inhibitors in mitral valve insufficiency. Patients and Methods Eighty patients (33 female/47 male, mean age 67 years) underwent cardiopulmonary bypass surgery for mitral valve reconstruction between 2007 and 2015. All patients suffered from mitral insufficiency (MI) Stages iii and iv. When tissue resection was acquired specimens were taken immediately frozen and used for histological examination. Expression of MMP‐1, MMP‐9, tissue inhibitor of metalloproteinase (TIMP)‐1, and TIMP‐2 was examined immunohistochemically and distribution was analyzed in regard to preoperative clinical, echocardiographic, and histopathological findings. Results A clear correlation between the MMP expression and the MI degree of severity could be shown. The expression of MMPs proved to be high in relation to mild insufficiencies and relatively weak in the case of severe ones. Additionally, the etiology of the MI was considered in the analysis and a significant difference in the expression of MMPs between the mitral valves with endocarditis and the ones featuring a degenerative disease could be shown. Within the group of valves with degenerative diseases, no significant difference could be established between the subgroups (myxoid and sclerosed valves). Conclusion The increased expression of MMPs and their inhibitors in mild insufficiencies could prove that the molecular changes in the valve precede the macroscopical and thus the echocardiographically diagnosable changes. Hence, new options for early diagnosis and therapy of MIs should be examined in further studies, respectively. Herein, the correlation of the MMP blood levels with MMP tissue expression should be addressed for surgical therapeutical decisions.

The role of the extracellular matrix in the development of heart valve disease: Underestimation or undercomprehension?

“…This marker, which is present on the endothelium of the heart valves in the left side but not in the right side of the cardiac structure, leads to remodeling of the extracellular matrix with an increased smooth muscle actin production. 13 Another study similar to Irqsusi et al 1 compared the tunica media of dilated PA with the normal pulmonary artery and aorta tissue, revealing downregulation of genes coding expression for proteins related to focal adhesion (e.g., paxillin), cytoskeleton (e.g., vimentin), and metalloproteinase-regulating proteoglycans (e.g., testican-2). 14 This downregulation was coupled with a marked decrease in microfibrilassociated glycoprotein 1, which controls elastic fiber accumulation.…”

“…17 No studies to date have long-term prospective data based on biomechanical modeling through the use of finite element analysis (FEA) and evaluation of morphostructure. Irqsusi et al 1 give us a window into this comparison, but to have a more integrated drawing, a prospective comparison is in order. This task will be first, nuanced by the fact that FEA is the primary method to acquire precious information about complex real-world systems that would otherwise be impossible to calculate directly.…”

“…In their recently published article, Irqsusi et al 1 explore the histopathology of extracellular matrix in the emergence of valvular pathologies, and more specifically, they investigate the role of selected matrix metalloproteinases and their inhibitors in mitral valve insufficiency. 1 This elegant retrospective study analyzing 80 patients is the first surgical versus immunohistochemical evaluation of two matrix metalloproteinases (MMP1 and MMP-9) and two inhibitors (TIMP-1 and TIMP-2).…”

“…In their recently published article, Irqsusi et al 1 explore the histopathology of extracellular matrix in the emergence of valvular pathologies, and more specifically, they investigate the role of selected matrix metalloproteinases and their inhibitors in mitral valve insufficiency. 1 This elegant retrospective study analyzing 80 patients is the first surgical versus immunohistochemical evaluation of two matrix metalloproteinases (MMP1 and MMP-9) and two inhibitors (TIMP-1 and TIMP-2). Patients suffering from severe mitral regurgitation ultrasonographically quantified as Grades I-III undergoing surgical valve repair due to endocarditis for 44% of cases while degenerative valve regurgitation was the primary pathology in 56% of patients.…”

“…This implies greater stress on the components of the extracellular matrix during circumferential and radial strains involving the mitral leaflets during chronic regurgitation (Figure 1). 1 At this stage of the scientific progress, a new path may be feasible in the diagnosis of degenerative mitral valve disease, thus, allowing differentiation of the myxomatous process associated with interrupted collagen fibers. 2…”