Genetics and Cardiovascular Development and Disease

A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425).

Deadline for manuscript submissions: closed (31 July 2015) | Viewed by 71418

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Guest Editor
Knight Cardiovascular Institute, Oregon Health & Science University, CH14M, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA
Interests: human cardiovascular genetics/genomics; genetically triggered thoracic aortic aneurysms; developmental basis of late onset cardiovascular diseases

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Guest Editor
Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
Interests: cardiac development; valve development; cardiovascular genetics; valve diseases; mitral valve prolapse; calcific aortic stenosis; ischemic MR; HOCM; myxomatous valves; fibroblast- myocyte interactions; fibrosis; primary cilia; cytoskeleton; membrane receptors; transcription factors
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Published Papers (10 papers)

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Research

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1352 KiB  
Article
MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions
by Damien Duval, Pauline Labbé, Léa Bureau, Thierry Le Tourneau, Russell A. Norris, Roger R. Markwald, Robert Levine, Jean-Jacques Schott and Jean Mérot
J. Cardiovasc. Dev. Dis. 2015, 2(3), 233-247; https://doi.org/10.3390/jcdd2030233 - 8 Sep 2015
Cited by 20 | Viewed by 5467
Abstract
Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the [...] Read more.
Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the first gene associated to non-syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1–8) of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST) as a specific binding partner of this region of FlnA protein. In addition, using yeast two-hybrid trap assay pull down and co-immunoprecipitation experiments, we showed that the MVP-associated FlnA mutations (G288R, P637Q, H743P) abolished FlnA/PTPN12 interactions. PTPN12 is a key regulator of signaling pathways involved in cell-extracellular matrix (ECM) crosstalk, cellular responses to mechanical stress that involve integrins, focal adhesion transduction pathways, and actin cytoskeleton dynamics. Interestingly, we showed that the FlnA mutations impair the activation status of two PTPN12 substrates, the focal adhesion associated kinase Src, and the RhoA specific activating protein p190RhoGAP. Together, these data point to PTPN12/FlnA interaction and its weakening by FlnA mutations as a mechanism potentially involved in the physiopathology of FlnA-associated MVP. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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5805 KiB  
Article
Dynamic Heterogeneity of the Heart Valve Interstitial Cell Population in Mitral Valve Health and Disease
by Tori E. Horne, Matthew VandeKopple, Kimberly Sauls, Sara N. Koenig, Lindsey J. Anstine, Vidu Garg, Russell A. Norris and Joy Lincoln
J. Cardiovasc. Dev. Dis. 2015, 2(3), 214-232; https://doi.org/10.3390/jcdd2030214 - 17 Aug 2015
Cited by 28 | Viewed by 7594
Abstract
The heart valve interstitial cell (VIC) population is dynamic and thought to mediate lay down and maintenance of the tri-laminar extracellular matrix (ECM) structure within the developing and mature valve throughout life. Disturbances in the contribution and distribution of valve ECM components are [...] Read more.
The heart valve interstitial cell (VIC) population is dynamic and thought to mediate lay down and maintenance of the tri-laminar extracellular matrix (ECM) structure within the developing and mature valve throughout life. Disturbances in the contribution and distribution of valve ECM components are detrimental to biomechanical function and associated with disease. This pathological process is associated with activation of resident VICs that in the absence of disease reside as quiescent cells. While these paradigms have been long standing, characterization of this abundant and ever-changing valve cell population is incomplete. Here we examine the expression pattern of Smooth muscle α-actin, Periostin, Twist1 and Vimentin in cultured VICs, heart valves from healthy embryonic, postnatal and adult mice, as well as mature valves from human patients and established mouse models of disease. We show that the VIC population is highly heterogeneous and phenotypes are dependent on age, species, location, and disease state. Furthermore, we identify phenotypic diversity across common models of mitral valve disease. These studies significantly contribute to characterizing the VIC population in health and disease and provide insights into the cellular dynamics that maintain valve structure in healthy adults and mediate pathologic remodeling in disease states. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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8378 KiB  
Article
Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease
by Kimberly Sauls, Katelynn Toomer, Katherine Williams, Amanda J. Johnson, Roger R. Markwald, Zoltan Hajdu and Russell A. Norris
J. Cardiovasc. Dev. Dis. 2015, 2(3), 200-213; https://doi.org/10.3390/jcdd2030200 - 24 Jul 2015
Cited by 26 | Viewed by 5850
Abstract
Mutations in the actin-binding gene Filamin-A have been linked to non-syndromic myxomatous valvular dystrophy and associated mitral valve prolapse. Previous studies by our group traced the adult valve defects back to developmental errors in valve interstitial cell-mediated extracellular matrix remodeling during fetal valve [...] Read more.
Mutations in the actin-binding gene Filamin-A have been linked to non-syndromic myxomatous valvular dystrophy and associated mitral valve prolapse. Previous studies by our group traced the adult valve defects back to developmental errors in valve interstitial cell-mediated extracellular matrix remodeling during fetal valve gestation. Mice deficient in Filamin-A exhibit enlarged mitral leaflets at E17.5, and subsequent progression to a myxomatous phenotype is observed by two months. For this study, we sought to define mechanisms that contribute to myxomatous degeneration in the adult Filamin-A-deficient mouse. In vivo experiments demonstrate increased infiltration of hematopoietic-derived cells and macrophages in adolescent Filamin-A conditional knockout mice. Concurrent with this infiltration of hematopoietic cells, we show an increase in Erk activity, which localizes to regions of MMP2 expression. Additionally, increases in cell proliferation are observed at two months, when hematopoietic cell engraftment and signaling are pronounced. Similar changes are observed in human myxomatous mitral valve tissue, suggesting that infiltration of hematopoietic-derived cells and/or increased Erk signaling may contribute to myxomatous valvular dystrophy. Consequently, immune cell targeting and/or suppression of pErk activities may represent an effective therapeutic option for mitral valve prolapse patients. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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757 KiB  
Article
Investigation of the Matrix Metalloproteinase-2 Gene in Patients with Non-Syndromic Mitral Valve Prolapse
by Maëlle Perrocheau, Soto Romuald Kiando, Déwi Vernerey, Christian Dina, Pilar Galan, Albert Hagege, Xavier Jeunemaitre and Nabila Bouatia-Naji
J. Cardiovasc. Dev. Dis. 2015, 2(3), 176-189; https://doi.org/10.3390/jcdd2030176 - 10 Jul 2015
Cited by 4 | Viewed by 5352
Abstract
Non-syndromic mitral valve prolapse (MVP) is a common degenerative valvulopathy, predisposing to arrhythmia and sudden death. The etiology of MVP is suspected to be under genetic control, as supported by familial cases and its manifestation in genetic syndrome (e.g., Marfan syndrome). One candidate [...] Read more.
Non-syndromic mitral valve prolapse (MVP) is a common degenerative valvulopathy, predisposing to arrhythmia and sudden death. The etiology of MVP is suspected to be under genetic control, as supported by familial cases and its manifestation in genetic syndrome (e.g., Marfan syndrome). One candidate etiological mechanism is a perturbation of the extracellular matrix (ECM) remodeling of the valve. To test this hypothesis, we assessed the role of genetic variants in the matrix metalloproteinase 2 gene (MMP2) known to regulate the ECM turnover by direct degradation of proteins and for which transgenic mice develop MVP. Direct sequencing of exons of MMP2 in 47 unrelated patients and segregation analyses in families did not reveal any causative mutation. We studied eight common single nucleotide polymorphisms (TagSNPs), which summarize the genetic information at the MMP2 locus. The association study in two case controls sets (NCases = 1073 and NControls = 1635) provided suggestive evidence for the association of rs1556888 located downstream MMP2 with the risk of MVP, especially in patients with the fibroelastic defiency form. Our study does not support the contribution of MMP2 rare variation in the etiology to MVP in humans, though further genetic and molecular investigation is required to confirm our current suggestive association of one common variant. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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3929 KiB  
Article
Altered Hemodynamics in the Embryonic Heart Affects Outflow Valve Development
by Vinal Menon, John F. Eberth, Richard L. Goodwin and Jay D. Potts
J. Cardiovasc. Dev. Dis. 2015, 2(2), 108-124; https://doi.org/10.3390/jcdd2020108 - 15 May 2015
Cited by 42 | Viewed by 7288
Abstract
Cardiac valve structure and function are primarily determined during early development. Consequently, abnormally-formed heart valves are the most common type of congenital heart defects. Several adult valve diseases can be backtracked to abnormal valve development, making it imperative to completely understand the process [...] Read more.
Cardiac valve structure and function are primarily determined during early development. Consequently, abnormally-formed heart valves are the most common type of congenital heart defects. Several adult valve diseases can be backtracked to abnormal valve development, making it imperative to completely understand the process and regulation of heart valve development. Epithelial-to-mesenchymal transition (EMT) plays an important role in the development of heart valves. Though hemodynamics is vital to valve development, its role in regulating EMT is still unknown. In this study, intracardiac hemodynamics were altered by constricting the outflow tract (OFT)/ventricle junction (OVJ) of HH16–17 (Hamilton and Hamburger (HH) Stage 16–17) chicken embryos, ex ovo for 24 h. The constriction created an increase in peak and time-averaged centerline velocity along the OFT without changes to volumetric flow or heart rate. Computational fluid dynamics was used to estimate the level of increased spatially-averaged wall shear stresses on the OFT cushion from AMIRA reconstructions. OFT constriction led to a significant decrease in OFT cushion volume and the number of invaded mesenchyme in the OFT cushion. qPCR analysis revealed altered mRNA expression of a representative panel of genes, vital to valve development, in the OFT cushions from banded hearts. This study indicates the importance of hemodynamics in valve development. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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773 KiB  
Communication
Rationale for the Cytogenomics of Cardiovascular Malformations Consortium: A Phenotype Intensive Registry Based Approach
by Robert B. Hinton, Kim L. McBride, Steven B. Bleyl, Neil E. Bowles, William L. Border, Vidu Garg, Teresa A. Smolarek, Seema R. Lalani and Stephanie M. Ware
J. Cardiovasc. Dev. Dis. 2015, 2(2), 76-92; https://doi.org/10.3390/jcdd2020076 - 29 Apr 2015
Cited by 12 | Viewed by 5360
Abstract
Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1%–5% of all live births. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are identified infrequently. In addition, a failure of systematic deep phenotyping of [...] Read more.
Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1%–5% of all live births. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are identified infrequently. In addition, a failure of systematic deep phenotyping of CVMs, resulting from the complexity and heterogeneity of malformations, has obscured genotype-phenotype correlations and contributed to a lack of understanding of disease mechanisms. To address these knowledge gaps, we have developed the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium, a multi-site alliance of geneticists and cardiologists, contributing to a database registry of submicroscopic genetic copy number variants (CNVs) based on clinical chromosome microarray testing in individuals with CVMs using detailed classification schemes. Cardiac classification is performed using a modification to the National Birth Defects Prevention Study approach, and non-cardiac diagnoses are captured through ICD-9 and ICD-10 codes. By combining a comprehensive approach to clinically relevant genetic analyses with precise phenotyping, the Consortium goal is to identify novel genomic regions that cause or increase susceptibility to CVMs and to correlate the findings with clinical phenotype. This registry will provide critical insights into genetic architecture, facilitate genotype-phenotype correlations, and provide a valuable resource for the medical community. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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5464 KiB  
Article
Targeted Mybpc3 Knock-Out Mice with Cardiac Hypertrophy Exhibit Structural Mitral Valve Abnormalities
by Daniel P. Judge, Hany Neamatalla, Russell A. Norris, Robert A. Levine, Jonathan T. Butcher, Nicolas Vignier, Kevin H. Kang, Quangtung Nguyen, Patrick Bruneval, Marie-Cécile Perier, Emmanuel Messas, Xavier Jeunemaitre, Annemarieke De Vlaming, Roger Markwald, Lucie Carrier and Albert A. Hagège
J. Cardiovasc. Dev. Dis. 2015, 2(2), 48-65; https://doi.org/10.3390/jcdd2020048 - 21 Apr 2015
Cited by 7 | Viewed by 6512
Abstract
MYBPC3 mutations cause hypertrophic cardiomyopathy, which is frequently associated with mitral valve (MV) pathology. We reasoned that increased MV size is caused by localized growth factors with paracrine effects. We used high-resolution echocardiography to compare Mybpc3-null, heterozygous, and wild-type mice (n [...] Read more.
MYBPC3 mutations cause hypertrophic cardiomyopathy, which is frequently associated with mitral valve (MV) pathology. We reasoned that increased MV size is caused by localized growth factors with paracrine effects. We used high-resolution echocardiography to compare Mybpc3-null, heterozygous, and wild-type mice (n = 84, aged 3–6 months) and micro-CT for MV volume (n = 6, age 6 months). Mybpc3-null mice showed left ventricular hypertrophy, dilation, and systolic dysfunction compared to heterozygous and wild-type mice, but no systolic anterior motion of the MV or left ventricular outflow obstruction. Compared to wild-type mice, echocardiographic anterior leaflet length (adjusted for left ventricular size) was greatest in Mybpc3-null mice (1.92 ± 0.08 vs. 1.72 ± 0.08 mm, p < 0.001), as was combined leaflet thickness (0.23 ± 0.04 vs. 0.15 ± 0.02 mm, p < 0.001). Micro-CT analyses of Mybpc3-null mice demonstrated increased MV volume (0.47 ± 0.06 vs. 0.15 ± 0.06 mm3, p = 0.018) and thickness (0.35 ± 0.04 vs. 0.12 ± 0.04 mm, p = 0.002), coincident with increased markers of TGFβ activity compared to heterozygous and wild-type littermates. Similarly, excised MV from a patient with MYBPC3 mutation showed increased TGFβ activity. We conclude that MYBPC3 deficiency causes hypertrophic cardiomyopathy with increased MV leaflet length and thickness despite the absence of left ventricular outflow-tract obstruction, in parallel with increased TGFβ activity. MV changes in hypertrophic cardiomyopathy may be due to paracrine effects, which represent targets for therapeutic studies. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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3109 KiB  
Article
N-acetylglucosamine-1-Phosphate Transferase Suppresses Lysosomal Hydrolases in Dysfunctional Osteoclasts: A Potential Mechanism for Vascular Calcification
by Yang Lei, Masaya Iwashita, Jung Choi, Masanori Aikawa and Elena Aikawa
J. Cardiovasc. Dev. Dis. 2015, 2(2), 31-47; https://doi.org/10.3390/jcdd2020031 - 15 Apr 2015
Cited by 8 | Viewed by 7002
Abstract
In addition to increased differentiation of vascular smooth muscle cells into osteoblast-like phenotypes, the limited accumulation of osteoclasts in atherosclerotic plaques or their dysfunction may participate in potential mechanisms for vascular calcification. N-acetylglucosamine-1-phosphate transferase containing alpha and beta subunits (GNPTAB) is a [...] Read more.
In addition to increased differentiation of vascular smooth muscle cells into osteoblast-like phenotypes, the limited accumulation of osteoclasts in atherosclerotic plaques or their dysfunction may participate in potential mechanisms for vascular calcification. N-acetylglucosamine-1-phosphate transferase containing alpha and beta subunits (GNPTAB) is a transmembrane enzyme complex that mediates the vesicular transport of lysosomal hydrolases. GNPTAB may also regulate the biogenesis of lysosomal hydrolases from bone-marrow derived osteoclasts. In this study, the areas surrounding calcification in human atherosclerotic plaques contained high levels of GNPTAB and low levels of lysosomal hydrolases such as cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP), as demonstrated by immunohistochemistry and laser-capture microdissection-assisted mRNA expression analysis. We therefore hypothesized that GNPTAB secretion may suppress the release of CTSK and TRAP by vascular osteoclast-like cells, thus causing their dysfunction and reducing the resorption of calcification. We used human primary macrophages derived from peripheral blood mononuclear cells, an established osteoclast differentiation model. GNPTAB siRNA silencing accelerated the formation of functional osteoclasts as detected by increased secretion of CTSK and TRAP and increased their bone resorption activity as gauged by resorption pits assay. We concluded that high levels of GNPTAB inhibit secretion of lysosomal hydrolases in dysfunctional osteoclasts, thereby affecting their resorption potential in cardiovascular calcification. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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Review

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3367 KiB  
Review
Embryonic Development of the Bicuspid Aortic Valve
by Peter S. Martin, Benjamin Kloesel, Russell A. Norris, Mark Lindsay, David Milan and Simon C. Body
J. Cardiovasc. Dev. Dis. 2015, 2(4), 248-272; https://doi.org/10.3390/jcdd2040248 - 2 Oct 2015
Cited by 50 | Viewed by 13568
Abstract
Bicuspid aortic valve (BAV) is the most common congenital valvular heart defect with an overall frequency of 0.5%–1.2%. BAVs result from abnormal aortic cusp formation during valvulogenesis, whereby adjacent cusps fuse into a single large cusp resulting in two, instead of the normal [...] Read more.
Bicuspid aortic valve (BAV) is the most common congenital valvular heart defect with an overall frequency of 0.5%–1.2%. BAVs result from abnormal aortic cusp formation during valvulogenesis, whereby adjacent cusps fuse into a single large cusp resulting in two, instead of the normal three, aortic cusps. Individuals with BAV are at increased risk for ascending aortic disease, aortic stenosis and coarctation of the aorta. The frequent occurrence of BAV and its anatomically discrete but frequent co-existing diseases leads us to suspect a common cellular origin. Although autosomal-dominant transmission of BAV has been observed in a few pedigrees, notably involving the gene NOTCH1, no single-gene model clearly explains BAV inheritance, implying a complex genetic model involving interacting genes. Several sequencing studies in patients with BAV have identified rare and uncommon mutations in genes of cardiac embryogenesis. But the extensive cell-cell signaling and multiple cellular origins involved in cardiac embryogenesis preclude simplistic explanations of this disease. In this review, we examine the series of events from cellular and transcriptional embryogenesis of the heart, to development of the aortic valve. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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975 KiB  
Review
Imaging of Mitral Valve Prolapse: What Can We Learn from Imaging about the Mechanism of the Disease?
by Ronen Durst and Dan Gilon
J. Cardiovasc. Dev. Dis. 2015, 2(3), 165-175; https://doi.org/10.3390/jcdd2030165 - 10 Jul 2015
Cited by 6 | Viewed by 6537
Abstract
Mitral valve prolapse (MVP) is the most common mitral valve disorder affecting 2%–3% of the general population. Two histological forms for the disease exist: Myxomatous degeneration and fibroelastic disease. Pathological evidence suggests the disease is not confined solely to the valve tissue, and [...] Read more.
Mitral valve prolapse (MVP) is the most common mitral valve disorder affecting 2%–3% of the general population. Two histological forms for the disease exist: Myxomatous degeneration and fibroelastic disease. Pathological evidence suggests the disease is not confined solely to the valve tissue, and accumulation of proteoglycans and fibrotic tissue can be seen in the adjacent myocardium of MVP patients. MVP is diagnosed by demonstrating valve tissue passing the annular line into the left atrium during systole. In this review we will discuss the advantages and limitations of various imaging modalities in their MVP diagnosis ability as well as the potential for demonstrating extra associated valvular pathologies. Full article
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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