Abstract 19746: Identification of Novel microRNA Profiles in Patients With Myxomatous Mitral Valve Disease

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michael A Hagler ◽  
Nassir M Thalji ◽  
Nate Russell ◽  
Michael Welge ◽  
Colleen Bushell ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Mitral Valve Disease ◽  
Cellular Proliferation ◽  
Valve Disease ◽  
Differentially Expressed ◽  
Matrix Remodeling ◽  
Mrna Levels ◽  
Mitral Valves ◽  
Mirna Sequencing ◽  
Upstream Regulators

Introduction: Myxomatous mitral valve disease (MMVD) is a degenerative condition characterized by tissue fibrosis and matrix remodeling which ultimately progresses to leaflet prolapse. While recent work has shown that transforming growth factor beta (TGF-β) signaling contributes to the pathogenesis of MMVD, upstream regulators of this and other pathways remain poorly understood. Hypothesis: We sought to use high-throughput RNA sequencing coupled with microRNA (miRNA) sequencing to identify novel molecular targets as well as upstream regulators contributing to MMVD. Methods: We conducted mRNA and miRNA sequencing on normal (n = 10) and myxomatous human mitral valve samples (n = 10). Differential expression was identified using linear modeling and parallel random forest analyses. Canonical pathways were identified by Ingenuity Pathway Analyses (IPA). Predicted miRNA targets were identified using TargetScanHuman 6.2. Results: We found 2784 mRNAs that were differentially expressed between normal and myxomatous mitral valves, which IPA largely categorized in to pro-fibrotic, matrix remodeling and cellular proliferation signaling. In miRNA sequenced from the same samples, 67 miRNAs were differentially-expressed between normal and myxomatous mitral valves. Increased expression of TGF-β ligands, collagen isoforms, and matrix metalloproteinases were associated with reductions in miRNAs predicted to target them. Conversely, mRNA levels of the “protective” genes TGFβ-induced factor homeobox 1, salt-inducible kinase 1, TIMP metallopeptidase inhibitor 4, and cyclin-dependent kinase inhibitor 1C mRNA levels were decreased in myxomatous tissue, and miRNAs predicted to target these genes (e.g., miR-656, miR-379-3p, miR-664a-3p, and miR-34c-5p) were significantly increased. Conclusions: Collectively, these data not only identify novel genes that are differentially regulated in MMVD, but also suggest miRNAs may play an active role in suppressing key protective molecules in MMVD. Thus, anti-mIRs therapy may be a viable therapeutic target to restore anti-fibrotic and anti-proliferative molecules in the valve and slow progression of MMVD. Future mechanistic studies will lay a critical foundation for translational work in these areas.

scholarly journals Comparative transcriptomic profiling of myxomatous mitral valve disease in the cavalier King Charles spaniel

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
G. R. Markby ◽  
V. E. Macrae ◽  
B. M. Corcoran ◽  
K. M. Summers
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Mitral Valve ◽  
Mitral Valve Disease ◽  
Expression Patterns ◽  
Valve Disease ◽  
Differentially Expressed ◽  
Gene Expression Patterns ◽  
Transcriptomic Profiling ◽  
Cavalier King Charles Spaniel

Abstract Background Almost all elderly dogs develop myxomatous mitral valve disease by the end of their life, but the cavalier King Charles spaniel (CKCS) has a heightened susceptibility, frequently resulting in death at a young age and suggesting that there is a genetic component to the condition in this breed. Transcriptional profiling can reveal the impact of genetic variation through differences in gene expression levels. The aim of this study was to determine whether expression patterns were different in mitral valves showing myxomatous degeneration from CKCS dogs compared to valves from non-CKCS dogs. Results Gene expression patterns in three groups of canine valves resulted in distinct separation of normal valves, diseased valves from CKCS and diseased valves from other breeds; the latter were more similar to the normal valves than were the valves from CKCS. Gene expression patterns in diseased valves from CKCS dogs were quite different from those in the valves from other dogs, both affected and normal. Patterns in all diseased valves (from CKCS and other breeds) were also somewhat different from normal non-diseased samples. Analysis of differentially expressed genes showed enrichment in GO terms relating to cardiac development and function and to calcium signalling canonical pathway in the genes down-regulated in the diseased valves from CKCS, compared to normal valves and to diseased valves from other breeds. F2 (prothrombin) (CKCS diseased valves compared to normal) and MEF2C pathway activation (CKCS diseased valves compared to non-CKCS diseased valves) had the strongest association with the gene changes. A large number of genes that were differentially expressed in the CKCS diseased valves compared with normal valves and diseased valves from other breeds were associated with cardiomyocytes including CASQ2, TNNI3 and RYR2. Conclusion Transcriptomic profiling identified gene expression changes in CKCS diseased valves that were not present in age and disease severity-matched non-CKCS valves. These genes are associated with cardiomyocytes, coagulation and extra-cellular matrix remodelling. Identification of genes that vary in the CKCS will allow exploration of genetic variation to understand the aetiology of the disease in this breed, and ultimately development of breeding strategies to eliminate this disease from the breed.

scholarly journals Novel Mechanisms Contributing to Fibrosis and Matrix Remodeling in Myxomatous Mitral Valve Disease

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Thomas M Hadley ◽  
Michael A Hagler ◽  
Hartzell V Schaff ◽  
Rakesh M Suri ◽  
Jordan D Miller
Keyword(s):  
Mitral Valve ◽  
Mitral Valve Disease ◽  
Valve Disease ◽  
Matrix Remodeling

scholarly journals Future Technology

2018 ◽  
Vol 23 (1) ◽  
pp. 123-133 ◽  
Author(s):  
Kelly Kohorst ◽  
Mias Pretorius
Keyword(s):  
Clinical Trials ◽  
Mitral Valve ◽  
Mitral Regurgitation ◽  
Minimally Invasive ◽  
Mitral Valve Disease ◽  
Open Heart Surgery ◽  
Mitral Annulus ◽  
Valve Disease ◽  
Mitral Valves ◽  
Transcatheter Mitral Valve Replacement

Mitral regurgitation is the most common valvular disease and significant (moderate/severe) mitral regurgitation is found in 2.3% of the population older than 65 years. New transcatheter minimally invasive technologies are being developed to address mitral valve disease in patients deemed too high a risk for conventional open-heart surgery. There are several features of the mitral valve (saddle-shaped noncalcified annulus with irregular leaflet geometry) that make a transcatheter approach to repair or replacing the valve more challenging compared with the aortic valve. Several devices are under investigation for transcatheter mitral valve replacement, and also for mitral valve repair targeting the mitral valve leaflets, chordae tendinae, and mitral annulus. The MitraClip device is the only Food and Drug Administration–approved device to treat mitral regurgitation by targeting the mitral leaflets. There are eight minimally invasive devices being studied in humans that target the mitral annulus, and at least two devices being studied in animal models. There are 5 devices in clinical trials for minimally invasive approaches targeting the chordae tendinae. More than 10 different transcatheter mitral valves are in various stages of development and clinical trials. These transcatheter mitral valves can be delivered either through a transseptal, transapical, transaortic, or left atriotomy approach. It seems likely that transcatheter treatment approaches to mitral valve disease will become more common, at least in the sick and elderly patient population.

Combined Valve Operations with Transection of Ascending Aorta

2002 ◽  
Vol 10 (4) ◽  
pp. 326-328
Author(s):  
Wen Lin Wang ◽  
Kai Can Cai ◽  
Wu Jun Wang
Keyword(s):  
Mitral Valve ◽  
Left Atrium ◽  
Mitral Valve Disease ◽  
Ascending Aorta ◽  
Aortic Annulus ◽  
Valve Disease ◽  
Intraoperative Bleeding ◽  
New Approach ◽  
Mitral Valves

To facilitate combined aortic and mitral valve operations, a new approach was developed. It was employed in 50 patients with both aortic and mitral valve disease. The ascending aorta was transected 1.5 cm above the aortic annulus, and the roof of the left atrium was incised. The damaged valves were replaced or repaired. Both aortic and mitral valves could be exposed satisfactorily by this approach. All patients recovered smoothly after the operation. Complications comprised intraoperative bleeding from the distal end of the ascending aorta in 1 patient and hoarseness in 3 postoperatively. The approach was considered quick and easy for combined valve operations.

scholarly journals Comparative transcriptomic profiling of myxomatous mitral valve disease in the Cavalier King Charles Spaniel

2020 ◽  
Author(s):  
Greg Markby ◽  
Vicky Macrae ◽  
Brendan Corcoran ◽  
Kim Summers
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Mitral Valve ◽  
Mitral Valve Disease ◽  
Expression Patterns ◽  
Valve Disease ◽  
Differentially Expressed ◽  
Gene Expression Patterns ◽  
Transcriptomic Profiling ◽  
Cavalier King Charles Spaniel

Abstract Background. Almost all elderly dogs develop myxomatous mitral valve disease by the end of their life, but the Cavalier King Charles Spaniel (CKCS) has a heightened susceptibility, frequently resulting in death at a young age and suggesting that there is a genetic component to the condition in this breed. Transcriptional profiling can reveal the impact of genetic variation through differences in gene expression levels. The aim of this study was to determine whether expression patterns were different in mitral valves showing myxomatous degeneration from CKCS dogs compared to valves from non-CKCS dogs. Results. Gene expression patterns in three groups of canine valves resulted in distinct separation of normal valves, diseased valves from CKCS and diseased valves from other breeds; the latter were more similar to the normal valves than were the valves from CKCS. Gene expression patterns in diseased valves from CKCS dogs were quite different from those in the valves from other dogs, both affected and normal. Patterns in all diseased valves (from CKCS and other breeds) were also somewhat different from normal non-diseased samples. Analysis of differentially expressed genes showed enrichment in GO terms relating to cardiac development and function and to calcium signalling canonical pathway in the genes down-regulated in the diseased valves from CKCS, compared to normal valves and to diseased valves from other breeds. F2 (prothrombin) (CKCS diseased valves compared to normal) and MEF2C pathway activation (CKCS diseased valves compared to non-CKCS diseased valves) had the strongest association with the gene changes. A large number of genes that were differentially expressed in the CKCS diseased valves compared with normal valves and diseased valves from other breeds were associated with cardiomyocytes including CASQ2, TNNI3 and RYR2. Conclusion. Transcriptomic profiling identified gene expression changes in CKCS diseased valves that were not present in age and disease severity-matched non-CKCS valves. These genes are associated with cardiomyocytes, coagulation and extra-cellular matrix remodelling. Identification of genes that vary in the CKCS will allow exploration of genetic variation to understand the aetiology of the disease in this breed, and ultimately development of breeding strategies to eliminate this disease from the breed.

scholarly journals Calcifications due to Mitral Valve Disease Induced by Rheumatoid Arthritis in K/B.g7 Mice

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Elena Konrath ◽  
Dr. Bryce Binstadt, M.D., Ph.D
Keyword(s):  
Rheumatoid Arthritis ◽  
Mitral Valve ◽  
Mitral Valve Disease ◽  
Late Onset ◽  
Valve Disease ◽  
Physiological Changes ◽  
Alizarin Red ◽  
Mitral Valves ◽  
Calcium Deposits ◽  
Potential Impact

Background and Hypothesis: Rheumatoid arthritis (RA) is a rheumatic autoimmune disease wherein the host generates self-antibodies that target the synovial lining of joints. However, it’s been observed that patients with RA also develop Mitral Valve Disease (MVD), although the mechanism is not very well known. In my project, I focused on the physiological changes of the heart during the formation of MVD, specifically focusing on calcifications and whether they form on the inflamed valve. I hypothesized that calcifications are developing during disease progression, resulting in advancement of the inflammation cycle. Experimental Design or Project Methods: A total of thirteen mouse hearts were removed and stored in OTC at -80 C: 5 K/B.g7 (7 months), 5 K/B.g7 (8 weeks) and 3 B6 (1.5 years). The hearts were sectioned and stained using calcium-staining Alizarin Red S. Additional sections were also stained with Hemotoxylin and Eosin stain. Results: From my analysis, it was apparent that there were no calcifications on the mitral valves in any of the samples. Pigmentation was apparent, but potential calcium was ruled out when compared to the H&E stains. There were heavy calcium deposits in the aorta and aortic valve in forty percent of the MVD samples. Additionally, calcium was seen near the apex of the left ventricle in three of the ten MVD samples. Conclusion and Potential Impact: In conclusion, it doesn’t appear that calcification occurs in the mitral valve, neither in the early nor late onset of RA. However, I pursued the calcifications seen in the aorta because of previous research done with calcifications seen in RA mice eating a high-fat diet. Currently, I am investigating further with the entirety of the aorta and staining to see if the calcification is isolated near the valve or if the calcifications spread. I am hoping that my findings will assist in identifying the physiological changes that are seen in rheumatoid arthritis.

scholarly journals Comparative transcriptomic profiling of myxomatous mitral valve disease in the Cavalier King Charles Spaniel

2020 ◽  
Author(s):  
Greg Markby ◽  
Vicky Macrae ◽  
Brendan Corcoran ◽  
Kim Summers
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Mitral Valve ◽  
Mitral Valve Disease ◽  
Expression Patterns ◽  
Valve Disease ◽  
Differentially Expressed ◽  
Gene Expression Patterns ◽  
Transcriptomic Profiling ◽  
Cavalier King Charles Spaniel

Abstract Background. Almost all elderly dogs develop myxomatous mitral valve disease by the end of their life, but the Cavalier King Charles Spaniel (CKCS) has a heightened susceptibility, frequently resulting in death at a young age and suggesting that there is a genetic component to the condition in this breed. Transcriptional profiling can reveal the impact of genetic variation through differences in gene expression levels. The aim of this study was to determine whether expression patterns were different in mitral valves showing myxomatous degeneration from CKCS dogs compared to valves from non-CKCS dogs. Results. Gene expression patterns in three groups of canine valves resulted in distinct separation of normal valves, diseased valves from CKCS and diseased valves from other breeds; the latter were more similar to the normal valves than were the valves from CKCS. Gene expression patterns in diseased valves from CKCS dogs were quite different from those in the valves from other dogs, both affected and normal. Patterns in all diseased valves (from CKCS and other breeds) were also somewhat different from normal non-diseased samples. Analysis of differentially expressed genes showed enrichment in GO terms relating to cardiac development and function and to calcium signalling canonical pathway in the genes down-regulated in the diseased valves from CKCS, compared to normal valves and to diseased valves from other breeds. F2 (prothrombin) (CKCS diseased valves compared to normal) and MEF2C pathway activation (CKCS diseased valves compared to non-CKCS diseased valves) had the strongest association with the gene changes. A large number of genes that were differentially expressed in the CKCS diseased valves compared with normal valves and diseased valves from other breeds were associated with cardiomyocytes including CASQ2, TNNI3 and RYR2. Conclusion. Transcriptomic profiling identified gene expression changes in CKCS diseased valves that were not present in age and disease severity-matched non-CKCS valves. These genes are associated with cardiomyocytes, coagulation and extra-cellular matrix remodelling. Identification of genes that vary in the CKCS will allow exploration of genetic variation to understand the aetiology of the disease in this breed, and ultimately development of breeding strategies to eliminate this disease from the breed.

scholarly journals Activation of the Interleukin-33/ST2 Pathway Exerts Deleterious Effects in Myxomatous Mitral Valve Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2310
Author(s):  
Amaia Garcia-Pena ◽  
Jaime Ibarrola ◽  
Adela Navarro ◽  
Alba Sadaba ◽  
Carolina Tiraplegui ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Mitral Valve ◽  
Mitral Valve Disease ◽  
Valve Disease ◽  
Proteoglycan Synthesis ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Interleukin 33 ◽  
Myxomatous Degeneration

Mitral valve disease (MVD) is a frequent cause of heart failure and death worldwide, but its etiopathogenesis is not fully understood. Interleukin (IL)-33 regulates inflammation and thrombosis in the vascular endothelium and may play a role in the atherosclerotic process, but its role in mitral valve has not been investigated. We aim to explore IL-33 as a possible inductor of myxomatous degeneration in human mitral valves. We enrolled 103 patients suffering from severe mitral regurgitation due to myxomatous degeneration undergoing mitral valve replacement. Immunohistochemistry of the resected leaflets showed IL-33 and ST2 expression in both valve interstitial cells (VICs) and valve endothelial cells (VECs). Positive correlations were found between the levels of IL-33 and molecules implicated in the development of myxomatous MVD, such as proteoglycans, extracellular matrix remodeling enzymes (matrix metalloproteinases and their tissue inhibitors), inflammatory and fibrotic markers. Stimulation of single cell cultures of VICs and VECs with recombinant human IL-33 induced the expression of activated VIC markers, endothelial–mesenchymal transition of VECs, proteoglycan synthesis, inflammatory molecules and extracellular matrix turnover. Our findings suggest that the IL-33/ST2 system may be involved in the development of myxomatous MVD by enhancing extracellular matrix remodeling.

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