Associations of Postoperative Hemoglobin Level and Clinical Outcomes in Patients Undergoing Mitral Valve Surgery.

BACKGROUND: Postoperative hemoglobin could indicate useful information for transfusion practices. The aim of this study was to investigate the association of optimal hemoglobin level and clinical outcomes after mitral valve surgery (MVS). METHODS: This investigation was a multicenter observational cohort study including 1,518 patients undergoing mitral valve surgery from 2016 through 2018. Patients were separated into six predefined groups based on initial postoperative hemoglobin (< 7.5 g/dL, 7.5 - 8.4 g/dL, 8.5 - 9.4 g/dL, 9.5 - 10.4 g/dL, 10.5 - 11.4 g/dL, ≥ 11.5 g/dL). Multivariable regression analysis was used to adjust laboratory results and surgical features of patients to evaluate the relationships between initial hemoglobin after MVS and clinical outcomes. RESULTS: Patients with initial postoperative hemoglobin below 7.5 g/dL had longer length of stays [mean (95% confidence interval [CI]), 1.9 (1.093 - 1.367)] in comparison with the reference group of 9.5 - 10.4 g/dL. Similarly, for those with hemoglobin below 7.5 g/dL, the odds (95% CI) for secondary outcomes included myocardial infraction 11.801 (1.353 - 22.966) and thrombosis 5.113 (1.340 - 9.508). However, for clinical outcomes, there was no significant difference between the five groups with hemoglobin greater than 7.5 g/dL. CONCLUSIONS: In patients after MVS, initial postoperative hemoglobin values below 7.5 g/dL was associated with worse outcomes compared to other values. Given similar outcomes between hemoglobin more than 7.5 g/dL groups, targeting treatment to an initial postoperative hemoglobin value at the lower value may be more desirable.

Optimized Protocol for the Extraction of Proteins from the Human Mitral Valve.

Analysis of the cellular proteome can help to elucidate the molecular mechanisms underlying diseases due to the development of technologies that permit the large-scale identification and quantification of the proteins present in complex biological systems.The knowledge gained from a proteomic approach can potentially lead to a better understanding of the pathogenic mechanisms underlying diseases, allowing for the identification of novel diagnostic and prognostic disease markers, and, hopefully, of therapeutic targets. However, the cardiac mitral valve represents a very challenging sample for proteomic analysis because of the low cellularity in proteoglycan and collagen-enriched extracellular matrix. This makes it challenging to extract proteins for a global proteomic analysis. This work describes a protocol that is compatible with subsequent protein analysis, such as quantitative proteomics and immunoblotting. This can allow for the correlation of data concerning protein expression with data on quantitative mRNA expression and non-quantitative immunohistochemical analysis. Indeed, these approaches, when performed together, will lead to a more comprehensive understanding of the molecular mechanisms underlying diseases, from mRNA to post-translational protein modification. Thus, this method can be relevant to researchers interested in the study of cardiac valve physiopathology.

Quantification and comparison of the mechanical properties of four human cardiac valves.

OBJECTIVE: Although having the same ability to permit unidirectional flow within the heart, the four main valves-the mitral valve (MV), aortic (AV), tricuspid (TV) and pulmonary (PV) valves-experience different loading conditions; thus, they exhibit different structural integrity from one another. Most research on heart valve mechanics have been conducted mainly on MV and AV or an individual valve, but none quantify and compare the mechanical and structural properties among the four valves from the same aged patient population whose death was unrelated to cardiovascular disease. METHODS: A total of 114 valve leaflet samples were excised from 12 human cadavers whose death was unrelated to cardiovascular disease (70.1±3.7years old). Tissue mechanical and structural properties were characterized by planar biaxial mechanical testing and histological methods. The experimental data were then fitted with a Fung-type constitutive model. RESULTS: The four valves differed substantially in thickness, degree of anisotropy, and stiffness. The leaflets of the left heart (the AV leaflets and the anterior mitral leaflets, AML) were significantly stiffer and less compliant than their counterparts in the right heart. TV leaflets were the most extensible and isotropic, while AML and AV leaflets were the least extensible and the most anisotropic. Age plays a significant role in the reduction of leaflet stiffness and extensibility with nearly straightened collagen fibers observed in the leaflet samples from elderly groups (65years and older). CONCLUSIONS: Results from 114 human leaflet samples not only provided a baseline quantification of the mechanical properties of aged human cardiac valves, but also offered a better understanding of the age-dependent differences among the four valves. It is hoped that the experimental data collected and the associated constitutive models in this study can facilitate future studies of valve diseases, treatments and the development of interventional devices. STATEMENT OF SIGNIFICANCE: Most research on heart valve mechanics have been conducted mainly on mitral and aortic valves or an individual valve, but none quantify and compare the mechanical and structural properties among the four valves from the same relatively healthy elderly patient population. In this study, the mechanical and microstructural properties of 114 leaflets of aortic, mitral, pulmonary and tricuspid valves from 12 human cadaver hearts were mechanically tested, analyzed and compared. Our results not only provided a baseline quantification of the mechanical properties of aged human valves, but a age range between patients (51-87years) also offers a better understanding of the age-dependent differences among the four valves. It is hoped that the obtained experimental data and associated constitutive parameters can facilitate studies of valve diseases, treatments and the development of interventional devices.

Lymphocyte-rich capillary-cavernous hemangioma of the mitral valve: a case report and review of the literature.

Valvular hemangioma incidence is extremely low. In this report, we describe a 62-year-old man who presented with mild edema of the lower limbs. An echocardiogram revealed an incidental 1.3-cm diameter mass on the anterior mitral valve leaflet for which he underwent surgical resection and mitral valve replacement. Histopathological examination showed a lymphocyte-rich capillary-cavernous hemangioma. The exuberant lymphoid stroma is unusual for hemangioma and represents an undescribed pattern of cardiac hemangioma. Including the present report, only 13 cases of mitral valve hemangioma have been reported to date. Most patients are adult. Mitral hemangioma originates in the atrial aspect of the valve and involves more commonly the anterior leaflet. The average maximum diameter of the lesion is 1.7 (S.D.=0.75) cm. Pure cavernous hemangioma is the predominant type of mitral hemangioma. Most of them are described as pedunculated or polypoid. Surgical excision appears to be curative. Recurrences have not been reported. Lymphocyte-rich cardiac hemangioma represents a peculiar type of hemangioma which should be included in the differential diagnosis of other vascular lesions.

Rheumatic Heart Disease and Myxomatous Degeneration: Differences and Similarities of Valve Damage Resulting from Autoimmune Reactions and Matrix Disorganization.

Autoimmune inflammatory reactions leading to rheumatic fever (RF) and rheumatic heart disease (RHD) result from untreated Streptococcus pyogenes throat infections in individuals who exhibit genetic susceptibility. Immune effector mechanisms have been described that lead to heart tissue damage culminating in mitral and aortic valve dysfunctions. In myxomatous valve degeneration (MXD), the mitral valve is also damaged due to non-inflammatory mechanisms. Both diseases are characterized by structural valve disarray and a previous proteomic analysis of them has disclosed a distinct profile of matrix/structural proteins differentially expressed. Given their relevance in organizing valve tissue, we quantitatively evaluated the expression of vimentin, collagen VI, lumican, and vitronectin as well as performed immunohistochemical analysis of their distribution in valve tissue lesions of patients in both diseases. We identified abundant expression of two isoforms of vimentin (45 kDa, 42 kDa) with reduced expression of the full-size protein (54 kDa) in RHD valves. We also found increased vitronectin expression, reduced collagen VI expression and similar lumican expression between RHD and MXD valves. Immunohistochemical analysis indicated disrupted patterns of these proteins in myxomatous degeneration valves and disorganized distribution in rheumatic heart disease valves that correlated with clinical manifestations such as valve regurgitation or stenosis. Confocal microscopy analysis revealed a diverse pattern of distribution of collagen VI and lumican into RHD and MXD valves. Altogether, these results demonstrated distinct patterns of altered valve expression and tissue distribution/organization of structural/matrix proteins that play important pathophysiological roles in both valve diseases.

Normal human mitral valve proteome: A preliminary investigation by gel-based and gel-free proteomic approaches.

The mitral valve is a highly complex structure which regulates blood flow from the left atrium to the left ventricle (LV) avoiding a significant forward gradient during diastole or regurgitation during systole. The integrity of the mitral valve is also essential for the maintenance of normal LV size, geometry, and function. Significant advances in the comprehension of the biological, functional, and mechanical behavior of the mitral valve have recently been made. However, current knowledge of protein components in the normal human mitral valve is still limited and complicated by the low cellularity of this tissue and the presence of high abundant proteins from the extracellular matrix. We employed here an integrated proteomic approach to analyse the protein composition of the normal human mitral valve and reported confident identification of 422 proteins, some of which have not been previously described in this tissue. In particular, we described the ability of pre-MS separation technique based on liquid-phase IEF and SDS-PAGE to identify the largest number of proteins. We also demonstrated that some of these proteins, e.g. αB-Crystallin, septin-11, four-and-a-half LIM domains protein 1, and dermatopontin, are synthesised by interstitial cells isolated from human mitral valves. These initial results provide a valuable basis for future studies aimed at analysing in depth the mitral valve protein composition and at investigating potential pathogenetic molecular mechanisms. Data are available via ProteomeXchange with identifier PXD004397.

Lymphangiogenesis is increased in heart valve endocarditis.

BACKGROUND: Inflammation-associated lymphangiogenesis (IAL) has been identified as part of several acute and chronic inflammation. Sparse data exist on lymphatics during endocarditis. MATERIALS AND METHODS: Fifty-two patients with surgically resected valves were included. Endocarditis was present in 18 aortic and 10 mitral valves. Controls consisted of 15 degenerative aortic and 9 degenerative mitral valves. There were 22 males with endocarditis and 17 males in controls. The mean age was 58 (SD 15) years with endocarditis vs. 62 (SD 13) years for controls. Lymphatics were detected by podoplanin antibody immunohistochemistry and morphometrical analysis was performed. RESULTS: The lymphatic density in endocarditis was 833 (SD 529) vessels/mm(2) (range 0-1707) as compared with 39 (SD 60) vessels/mm(2) (range 0-250) in controls (p=0.000). In endocarditis, the mean lymphatic size was 153 (SD 372) µm(2) ranging from 1 to 2034µm(2), whereas it was 30 (SD 29) µm(2), with maximum 90µm(2) and minimum 2µm(2) in controls (p=0.000). CONCLUSIONS: IAL is increased in valves with endocarditis as compared with controls. Lymphatics in heart valves may provide a novel means for treatment strategies against endocarditis.

Comparative Histopathological Analysis of Mitral Valves in Barlow Disease and Fibroelastic Deficiency.

Whether Barlow disease (BD) and fibroelastic deficiency (FED), the main causes of mitral valve prolapse (MVP), should be considered 2 distinct diseases remains unknown. Mitral valves from patients who required surgery for severe mitral regurgitation due to degenerative nonsyndromic MVP were analyzed. Intraoperative diagnosis of BD or FED was based on leaflet redundancy and thickness, number of segments involved, and annular dimension. The removed medial scallop of the posterior leaflet and attached chordae were used for histopathological and immunohistological assessment. Histologically, compared to normal controls (n = 3), BD (n = 14), and FED (n = 9) leaflets demonstrated an altered architecture and increased thickness. Leaflet thickness was greater and chordae thickness lower in BD than FED (P < 0.0001). In BD, increased thickness was owing to spongiosa expansion (proteoglycan accumulation) and intimal thickening on fibrosa and atrialis; in FED, local thickening was predominant on the fibrosa side, with accumulation of proteoglycan-like material around the chordae. Collagen accumulation was observed in FED leaflets and chords and decreased in BD. Fragmented elastin fibers were present in BD and FED; elastin decreased in BD but increased in FED leaflets and around chordae. Activated myofibroblasts accumulate in both diseased leaflets and chords, but more abundantly in FED chordae (P < 0.0001), independently of age, suggesting a role of these cells in chordal rupture. There were more CD34-positive cells in BD leaflets and in FED chordae (P < 0.01). In BD leaflets (but not chordae) proliferative Ki67-positive cells were more abundant (P < 0.01) and matrix metalloproteinase 2 levels were increased (P < 0.01) indicating tissue remodeling. Upregulation of transforming growth factor beta and pERK signaling pathways was evident in both diseases but more prominent in FED leaflets (continued on next page)(P < 0.001), with pERK upregulation in FED chordae (P < 0.0001). Most cellular and signaling markers were negligible in control valves. Quantitative immunohistopathological analyses demonstrated distinct changes between BD and FED valves: predominant matrix degradation in BD and increased profibrotic signaling pathways in FED, indicating that BD and FED are 2 different entities. These results may pave the way for genetic studies of MVP and development of preventive drug therapies.

TGF-beta1 pathway activation and adherens junction molecular pattern in nonsyndromic mitral valve prolapse.

AIMS: Dysregulation of the transforming growth factor beta (TGF-ß) 1 pathway has been associated with either syndromic or isolated mitral valve (MV) prolapse due to myxoid degeneration (floppy MV). The activation of Smad receptor-mediated intracellular TGF-ß pathway and its effect on adherens junction (AJ) molecular pattern of activated valvular interstitial cells (VICs) in MV prolapse are herein investigated. METHODS: Floppy MV leaflets were obtained from 30 patients (24 males, mean age 55.5±12.7 years) who underwent surgical repair, and 10 age- and sex-matched Homograft Tissue Bank samples served as controls. MV leaflet cellular and extracellular matrix composition, including collagen I and III, was evaluated by histology and transmission electron microscopy. Smad2 active phosphorylated form (p-Smad2), α-smooth muscle actin (α-SMA), and junctional proteins (N-cadherin, cadherin-11, ß-catenin, plakoglobin, plakophilin-2) in VICs were assessed by immunohistochemistry and immunofluorescence and confirmed by immunoblotting. Quantitative real-time polymerase chain reaction was carried out for components of TGF-ß pathway cascade and filamin A (FLN-A). RESULTS: Floppy MV leaflets were thicker (P<.001) and had higher α-SMA+ cell density (P=.002) and collagen III expression (P<.001) than controls. Enhanced p-Smad2 nuclear immunoreactivity (P<.001) and TGF-ß1 gene (P=.045), TIMP1 (P=.020), and CTGF (P=.047) expression but no differences in FLN-A and total Smad2 gene expression levels were found between floppy MV and controls. Higher expression of cadherin-11, either exclusively or in colocalization with N-cadherin, and aberrant presence of plakophilin-2 at the AJ were found in floppy MV vs. CONCLUSIONS: TGF-ß1 pathway activation in nonsyndromic MV prolapse induces VICs differentiation into contractile myofibroblasts and is associated with changes in the molecular pattern of the AJ, with increased cadherin-11 and aberrant plakophilin-2 expression. AJ reinforcement might promote latent TGF-ß1 activation leading to extracellular matrix remodeling in floppy MV.

The Role of Interleukin-13 in Patients with Rheumatic Valvular Fibrosis: A Clinical and Histological Study.

BACKGROUND AND AIM OF THE STUDY: Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious diseases, yet few studies have reported its role in valvular fibrosis in patients with rheumatic heart disease (RHD). The study aim was to investigate the role of IL-13 in mitral valvular fibrosis in patients with RHD. METHODS: Peripheral blood samples were collected from surgical patients with RHD (n = 18) and from healthy controls (n = 9). Serum levels of IL-13 and interferon (IFN)-gamma were analyzed using ELISA. Rheumatic mitral valves removed from surgical patients with RHD, and normal mitral valves, were obtained at autopsy. The expression and distribution of collagen I, collagen III, and IL-13Ralpha1 were examined by immunohistochemical staining, the degree of which was measured using computed imaging analysis. RESULTS: Higher IL-13 levels were observed in RHD patients (15.16 +/- 9.62 pg/ml; p < 0.05) than in healthy controls (7.78 +/- 3.87 pg/ml). RHD patients had high levels of IFN-gamma (9.95 +/- 0.77 pg/ml; p <0.05) compared to healthy controls (5.95 +/- 0.69 pg/ml). Immunohistochemistry showed that, compared to normal valves, rheumatic mitral valves expressed high levels of collagen I (0.01931 +/- 0.00159 versus 0.01183 +/- 0.00207; p < 0.05), collagen III (0.00726 +/- 0.00078 versus 0.00342 +/- 0.00124; p <0.05), and IL-13Rcxl (0.00454 +/- 0.00086 versus 0.00017 +/- 0.00008; p <0.01). Collagens I and III were each expressed in heart interstitial cells, while IL-13Ralpha1 was expressed in the endothelial cells and smooth muscle cells of the blood vessels, and in interstitial cells. CONCLUSION: Patients with RHD showed increased serum levels of IL-13 compared to healthy controls. IFN-gamma levels were clearly different among RHD patients and healthy controls. The expression of collagens I and III and IL-13Ralpha1 was higher in rheumatic mitral valves compared to normal mitral valves. IL-13 may induce mitral valvular fibrosis in RHD.

Serotonin concentrations in platelets, plasma, mitral valve leaflet, and left ventricular myocardial tissue in dogs with myxomatous mitral valve disease.

HYPOTHESIS/OBJECTIVES: Altered serotonin (5-hydroxytryptamine, 5HT) signaling is postulated in development and progression of canine myxomatous mitral valve disease (MMVD). Little is known regarding platelet, plasma, valvular, or myocardial 5HT concentration ([5HT]) in affected dogs. We quantified [5HT] in platelet-rich plasma (PRP), platelet-poor plasma (PPP), mitral valve leaflets (MV), and left ventricular myocardium (LV). ANIMALS: Forty-five dogs comprised 4 plasma groups of Cavalier King Charles Spaniels (CKCS) or non-CKCS, either healthy (CON) or MMVD affected: CKCS CON (n = 12); non-CKCS CON (n = 8); CKCS MMVD (n = 14); non-CKCS MMVD (n = 11). Twenty-four dogs comprised 3 tissue groups: MMVD (n = 8); other-HD (heart disease) (n = 7); non-HD, extracardiac disease (n = 9). METHODS: High-performance liquid chromatography measured PRP, PPP, MV, and LV [5HT]. RESULTS: Platelet-rich plasma platelet [5HT] was greater in CKCS CON (1.83 femtograms/platelet [fg/plt]; range, 0.20-4.76; P = .002), CKCS MMVD (1.58 fg/plt; range, 0.70-4.03; P = .005), and non-CKCS MMVD (1.72 fg/plt; range, 0.85-4.44; P = .003) versus non-CKCS CON (0.92 fg/plt; range, 0.63-1.30). There was no group difference in PPP [5HT]. MV [5HT] was significantly higher in MMVD (32.4 ng/mg; range, 8.4-106.7) versus non-HD (3.6 ng/mg; range, 0-28.3; P = .01) and LV [5HT] was significantly higher in MMVD (11.9 ng/mg; range, 4.0-104.8) versus other-HD (0.9 ng/mg; range, 0-10.1; P = .011) and non-HD (2.5 ng/mg; range, 0-6.9; P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Platelet [5HT] was highest in healthy CKCS and both MMVD groups, but plasma [5HT] showed no group differences. Tissue [5HT] was highest in MV and LV of MMVD-affected dogs, suggesting altered 5HT signaling as a potential feature of MMVD. Interactions of platelet, valvular, and myocardial 5HT signaling warrant further investigation.

Clinical and pathological features of degenerative mitral valve disease: billowing mitral leaflet versus fibroelastic deficiency.

PURPOSE: Degenerative mitral valve disease is distinguished with billowing mitral leaflet (BML) or fibroelastic deficiency (FED). The purpose of this study is to evaluate the clinical characteristics and the pathohistological differences between BML and FED. METHODS: A total of 73 patients who diagnosed as degenerative mitral valve disease pathologically after mitral valve surgery for severe mitral regurgitation were enrolled. On the basis of echocardiographic features and gross appearances, they were classified as BML (9 cases) and FED (64 cases). RESULTS: In the BML group, multiple segments of the leaflet showed billowing with elongated chordae. Therefore excessive valve tissue needed to be removed by multiple resection and suture. The FED patients had focal myxomatous changes with ruptured chordae, a single resection and suture was frequently employed. In pathological examination, the valve thickness of the BML was nearly twice as thick as the FED, and the mucopolysaccharide accumulation of the Spongiosa in the BML was over 50%, while 30% in the FED. CONCLUSION: BML presents the characteristic valve thickening due to its abnormal production of mucopolysaccharide. Since excessive tissue was voluminous in the BML, high-grade plasty techniques, such as combination of multiple resection and chordal reconstruction were required.

A case of mesothelial/monocytic incidental cardiac excrescence and literature review.

Mesothelial/monocytic incidental cardiac excrescence (MICE) is a rare entity which is an amalgam of mesothelial cells, histiocytes, and fibrin, often found occasionally during cardiac valve replacement. We report a case in a 25-year-old Chinese female with serous mitral stenosis and patent foramen ovale. Routine and immunohistochemical stains and ultrastructure examination revealed the vegetation was predominantly composed of histocytes with scattered mesothelial cells. In fact nodular histiocytic/mesothelial hyperplasia (NHMH) is a similar lesion to MICE. MICE and NHMH could be unified, and NHMH may be a better choice.

Heart valve collagens: cross-species comparison using immunohistological methods.

BACKGROUND AND AIM OF THE STUDY: Tissue engineering is an emerging strategy for the development of replacement heart valves where the properties of native tissues are to be replicated. The complexity of the distribution of various collagens in the aortic, mitral, and pulmonary valve leaflets of porcine, bovine, and ovine origin, has been examined. METHODS: Immunohistological and transmission electron microscopy analyses using monoclonal antibodies to types I, III, IV, V and VI collagens were performed. RESULTS: The results indicated that each collagen type has its own distinct distribution, with minimal variation between heart valve anatomic sites and species. Of particular interest was type VI collagen, which had an asymmetric distribution that was principally localized along the outflow surface of the valve. CONCLUSION: Successful tissue engineering constructs of heart valves may need to replicate the complex distribution of different collagens found in heart valve tissues.

Ubiquitin-positive foam cells are identified in the aortic and mitral valves with atherosclerotic involvement.

AIM: Our aim was to determine the roles of the ubiquitin (Ub)-proteasome system (UPS) in valvular diseases by immunohistochemically identifying Ub-positive cells in aortic and mitral valves and determining if Ub+cells were associated with the severity of valvular diseases. METHODS: We evaluated surgically removed aortic and mitral valves from 60 patients (mean age, 64.5 years) for thickening, fibrosis, foam cell infiltration, thrombus, and atheromatous plaques by using grading scores. U+cells were detected immunohistochemically. RESULTS: We found Ub+cells in 16 (26.7%) of the 60 patients. Eleven (28.2%) of the 39 aortic valves and 5 (23.8%) of the 21 mitral valves were Ub-positive. Ub was found with granular depositions in the cytoplasm of monocyte-derived foam cells that were CD68+. The aortic valvular thickness of the Ub+group was significantly greater than that of the Ub- group (3.9+/-1.6mm vs. 3.2+/-1.6mm, p<0.05). Foam cells and fibrosis were greater in the Ub+group (p<0.05), and calcifications were prominent in aortic valves. There was no difference in the number of apoptotic cells in Ub+ and Ub- groups. Ub+cells were present in the affected valves and ubiquitinated proteins were accumulated in macrophage-derived foam cells. CONCLUSIONS: Ub+ foam cells are present in valves that are vulnerable to valvular disease, and UPS may contribute to the development of atherosclerosis through the inflammatory process.

Significant changes in mitral valve leaflet matrix composition and turnover with tachycardia-induced cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) involves significant remodeling of the left ventricular-mitral valve (MV) complex, but little is known regarding the remodeling of the mitral leaflets. The aim of this study was to assess changes in matrix composition and turnover in MV leaflets with DCM. METHODS AND RESULTS: Radiopaque markers were implanted in 24 sheep to delineate the MV; 10 sheep underwent tachycardia-induced cardiomyopathy (TIC), whereas 14 sheep remained as controls. Biplane videofluoroscopy was performed before and after TIC. Immunohistochemistry was performed on leaflet cross-sections taken from the septal, lateral, anterior, and posterior commissures attachment segments. Staining intensity was quantified within each attachment segment and leaflet region (basal, mid-leaflet, and free edge). Mitral regurgitation increased from 0.2+/-0.4 before TIC to 2.2+/-0.9 after TIC (P<0.0002). TIC leaflets demonstrated significant remodeling compared to controls, including greater cell density and loss of leaflet layered structure (all P<0.05). Collagen and elastic fiber turnover was greater in TIC, as was the myofibroblast phenotype (all P<0.05). Compositional differences between TIC and control leaflets were heterogeneous by annular segment and leaflet region, and related to regional changes in leaflet segment length with TIC. CONCLUSIONS: This study shows that the MV leaflets are significantly remodeled in DCM with changes in leaflet composition, structure, and valve cell phenotype. Understanding how alterations in leaflet mechanics, such as those induced by DCM, drive cell-mediated remodeling of the extracellular matrix will be important in developing future treatment strategies.

Abundance and location of proteoglycans and hyaluronan within normal and myxomatous mitral valves.

INTRODUCTION: Extracellular matrix changes occur in many heart valve pathologies. For example, myxomatous mitral valves are reported to contain excess proteoglycans and hyaluronan. However, it is unknown which specific proteoglycans are altered in myxomatous valves. Because proteoglycans perform varied functions in connective tissues, this study was designed to identify and localize three matrix-associated proteoglycans, as well as hyaluronan and the hyaluronan receptor for endocytosis, within myxomatous and normal mitral valves. METHODS: Human mitral posterior leaflets (control, n=6-9; myxomatous, n=14-21; mean age, 61 years for all groups) were histochemically stained for proteoglycan core proteins, hyaluronan, and the hyaluronan receptor for endocytosis. Stain intensity was semiquantitatively graded to determine differences in marker abundance between normal and myxomatous valves. The proteoglycans were localized to different regions of the leaflet by correspondence to parallel Movat-stained sections. RESULTS: The proteoglycans decorin, biglycan, and versican were more abundant in myxomatous valves than in normal controls (P<.03). There was a gender effect on proteoglycan presence, but no age-related trends were observed. Hyaluronan and the hyaluronan receptor for endocytosis were distributed throughout all valves. There was no significant difference in hyaluronan between groups, but expression of the hyaluronan receptor for endocytosis was reduced in myxomatous valves compared to normal controls (P<.002). CONCLUSION: Excess decorin, biglycan, and versican may be associated with the remodeling of other matrix components in myxomatous mitral valves. Decreased expression of the hyaluronan receptor for endocytosis in myxomatous valves suggests that hyaluronan metabolism could be altered in myxomatous mitral valve disease. These findings contribute towards elucidating the pathogenesis of myxomatous mitral valve disease and developing potential new therapies.

PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients.

Rheumatic fever (RF) is a post-infectious autoimmune disease due to sequel of group A streptococcus (GAS) pharyngitis. Rheumatic heart disease (RHD), the major manifestation of RF, is characterized by inflammation of heart valves and myocardium. Molecular mimicry between GAS antigens and host proteins has been shown at B and T cell level. However the identification of the autoantigens recognized by B and T cells within the inflammatory microenvironment of heart tissue in patients with RHD is still incompletely elucidated. In the present study, we used two-dimensional gel electrophoresis (2-DE) and mass spectrometry to identify valvular tissue proteins target of T cells from chronic RHD patients. We could identify three proteins recognized by heart infiltrating and peripheral T cells as protein disulfide isomerase ER-60 precursor (PDIA3), 78kD glucose-regulated protein precursor (HSPA5) and vimentin, with coverage of 45%, 43 and 34%, respectively. These proteins were recognized in a proliferation assay by peripheral and heart infiltrating T cells from RHD patients suggesting that they may be involved in the autoimmune reactions that leads to valve damage. We also observed that several other proteins isolated by 2-DE but not identified by mass spectrometry were also recognized by T cells. The identified cardiac proteins are likely relevant antigens involved in T cell-mediated autoimmune responses in RF/RHD that may contribute to the development of RHD.

[Myxomatous mitral valve degeneration: biochemical aspects and physiopathological considerations]. / L'insuffisance mitrale par dégénerescence myxoïde: aspect biochimique et considérations physiopathologiques.

Mitral valve is a complex structure which is submitted to repeated mechanical constraints. In clinical practice, an increasing incidence of mitral insufficiency resulting from myxomatous degeneration is observed. Since myxomatous degeneration is also observed in defined genetic diseases of connective tissues, we propose the hypothesis that idiopathic mitral insufficiency might result from a minor alteration of the interstitial valvular cells and/or their interactions with their support. After a brief review of the role of the extracellular matrix in the heart, some histopathological and biochemical aspects of myxomatous degeneration are presented. Our data and those of the literature will be summarized and a physiopathological hypothesis proposed for myxomatous mitral valve degeneration.