ABSTRACT
RATIONALE: Mitral valve prolapse (MVP) is one of the most common valvular disorders. However, the molecular and cellular mechanisms involved in fibromyxomatous changes in the mitral leaflet tissue have not been elucidated. Aldosterone (Aldo) promotes fibrosis in myocardium, and MR (mineralocorticoid receptor) antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis. OBJECTIVE: We investigated the role of the Aldo/MR in the fibromyxomatous modifications associated with MVP. METHODS AND RESULTS: Aldo enhanced valvular interstitial cell activation markers and induced endothelial-mesenchymal transition in valvular endothelial cells, resulting in increased proteoglycan secretion. MRA blocked all the above effects. Cytokine arrays showed CT-1 (cardiotrophin-1) to be a mediator of Aldo-induced valvular interstitial cell activation and proteoglycan secretion and CD (cluster of differentiation) 14 to be a mediator of Aldo-induced endothelial-mesenchymal transition and proteoglycan secretion in valvular endothelial cells. In an experimental mouse model of MVP generated by nordexfenfluramine administration, MRA treatment reduced mitral valve thickness and proteoglycan content. Endothelial-specific MR deletion prevented fibromyxomatous changes induced by nordexfenfluramine administration. Moreover, proteoglycan expression was slightly lower in the mitral valves of MVP patients treated with MRA. CONCLUSIONS: These findings demonstrate, for the first time, that the Aldo/MR pathway regulates the phenotypic, molecular, and histological changes of valvular interstitial cells and valvular endothelial cells associated with MVP development. MRA treatment appears to be a promising option to reduce fibromyxomatous alterations in MVP.
Subject(s)
Aldosterone/toxicity , Mitral Valve Prolapse/metabolism , Mitral Valve/drug effects , Receptors, Mineralocorticoid/agonists , Receptors, Mineralocorticoid/metabolism , Aged , Animals , Case-Control Studies , Cell Differentiation/drug effects , Cells, Cultured , Cytokines/metabolism , Disease Models, Animal , Epithelial-Mesenchymal Transition/drug effects , Female , Fibrosis , Humans , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Mineralocorticoid Receptor Antagonists/pharmacology , Mitral Valve/metabolism , Mitral Valve/pathology , Mitral Valve Prolapse/chemically induced , Mitral Valve Prolapse/pathology , Mitral Valve Prolapse/prevention & control , Paracrine Communication , Phenotype , Prospective Studies , Proteoglycans/metabolism , Receptors, Mineralocorticoid/deficiency , Receptors, Mineralocorticoid/genetics , Signal TransductionABSTRACT
The need for more detail regarding the clinical and morphological features of human heart valves has become evident due to recent controversy regarding anorexigen-associated valvular dysfunction. In the present study, we used quantitative digital image analysis of geometric and compositional features to compare the histopathology of cardiac valves excised from patients treated with anorexigens as compared to normal, floppy, rheumatic and carcinoid valves. Anorexigen-exposed valves had the greatest number of onlays/valve (P<.0001), while rheumatic valves showed the greatest average onlay size and thickness of the comparison groups studied (P=.01). The valve onlays from anorexigen-exposed, carcinoid and floppy valves contained a greater percentage of glycosaminoglycans (GAGs) as compared to normal and rheumatic valves (P=.01). The anorexigen-exposed valve propers contained more GAGs than any other comparison group (P=.02). Vessels were prominent in both onlay and valve proper regions of carcinoid valves, in the anorexigen-exposed valve onlays and in rheumatic valve propers. Thus, the number of onlays, their size, the degree of GAG deposition, and the presence and location of vessels and leukocytes were important features distinguishing anorexigen-exposed valves from normal valves. Discriminant analyses, based on geometry, color composition or color composition, and vessel and leukocyte counts combined, were able to separate the valves into distinguishable groups. Our findings demonstrate that specific microscopic features can be used to separate anorexigen-associated heart valve lesions from normal valves and valve lesions associated with other pathologies, and suggest that a distinctive pathological process may exist in many anorexigen-exposed valves.
Subject(s)
Appetite Depressants/adverse effects , Heart Valve Diseases/diagnosis , Heart Valves/drug effects , Heart Valves/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoid Heart Disease/complications , Carcinoid Heart Disease/metabolism , Carcinoid Heart Disease/pathology , Discriminant Analysis , Female , Fenfluramine/adverse effects , Glycosaminoglycans/metabolism , Heart Valve Diseases/chemically induced , Heart Valve Diseases/metabolism , Heart Valves/metabolism , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Mitral Valve Prolapse/chemically induced , Mitral Valve Prolapse/metabolism , Mitral Valve Prolapse/pathology , Phentermine/adverse effects , Rheumatic Heart Disease/complications , Rheumatic Heart Disease/metabolism , Rheumatic Heart Disease/pathologyABSTRACT
The recent identification of a new type of anxiety state, panic attack, has drawn attention to common pathways between panic disorder and cardiac somatization, particularly mitral valve collapse. A double-blind study was set up, using doppler-echocardiography during a panic attack induced by sodium lactate infusion. The results showed that there was no relationship between panic attack and mitral valve collapse, and that the lactate infusion-anxiety rate was only 35 percent.
