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J. Cardiovasc. Dev. Dis., Volume 2, Issue 2 (June 2015) – 7 articles , Pages 31-140

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Review
Neutron Scattering at the Intersection of Heart Health Science and Biophysics
by Drew Marquardt, Richard J. Alsop, Maikel C. Rheinstädter and Thad A. Harroun
J. Cardiovasc. Dev. Dis. 2015, 2(2), 125-140; https://doi.org/10.3390/jcdd2020125 - 02 Jun 2015
Cited by 3 | Viewed by 7148
Abstract
There is an urgent quest for improved heart health. Here, we review how neutron radiation can provide insight into the molecular basis of heart health. Lower cholesterol, a daily intake of aspirin and supplemental vitamin E are argued to all improve heart health. [...] Read more.
There is an urgent quest for improved heart health. Here, we review how neutron radiation can provide insight into the molecular basis of heart health. Lower cholesterol, a daily intake of aspirin and supplemental vitamin E are argued to all improve heart health. However, the mechanisms behind these common regimens, and others, are not entirely understood. It is not clear why a daily intake of aspirin can help some people with heart disease, and the benefits of vitamin E in the treatment of reperfusion injury have been heavily debated. The molecular impact of cholesterol in the body is still a hot topic. Neutron scattering experiments present a unique opportunity for biophysicists attempting to address these problems. We review some recently published studies that are advancing our understanding of how cholesterol, vitamin E and aspirin work at the molecular level, by studying the impact of these molecules on the cell membrane. These insights engage the broader health science community with new ways of thinking about these molecules. Full article
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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 6739
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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Article
Advanced Electrocardiography Identifies Left Ventricular Systolic Dysfunction in Non-Ischemic Cardiomyopathy and Tracks Serial Change over Time
by Kerryanne Johnson, Stacey Neilson, Andrew To, Nezar Amir, Andrew Cave, Tony Scott, Martin Orr, Mia Parata, Victoria Day and Patrick Gladding
J. Cardiovasc. Dev. Dis. 2015, 2(2), 93-107; https://doi.org/10.3390/jcdd2020093 - 13 May 2015
Cited by 9 | Viewed by 5481
Abstract
Electrocardiogram (ECG)-based detection of left ventricular systolic dysfunction (LVSD) has poor specificity and positive predictive value, even when including major ECG abnormalities, such as left bundle branch block (LBBB) within the criteria for diagnosis. Although machine-read ECG algorithms do not provide information on [...] Read more.
Electrocardiogram (ECG)-based detection of left ventricular systolic dysfunction (LVSD) has poor specificity and positive predictive value, even when including major ECG abnormalities, such as left bundle branch block (LBBB) within the criteria for diagnosis. Although machine-read ECG algorithms do not provide information on LVSD, advanced ECG (A-ECG), using multiparameter scores, has superior diagnostic utility to strictly conventional ECG for identifying various cardiac pathologies, including LVSD. Methods: We evaluated the diagnostic utility of A-ECG in a case-control study of 40 patients with LVSD (LV ejection fraction < 50% by echocardiography), due to non-ischemic cardiomyopathy (NICM), and 39 other patients without LVSD. Diagnostic sensitivity and specificity for LVSD were determined after applying a previously validated probabilistic A-ECG score for LVSD to stored standard (10 s) clinical 12L ECGs. In 25 of the NICM patients who had serial ECGs and echocardiograms, changes in the A-ECG score versus in echocardiographic LV ejection fraction were also studied to determine the level of agreement between the two tests. Results: Analyses by A-ECG had a sensitivity of 95% for LVSD (93% if excluding N = 11 patients with LBBB) and specificity of 95%. In the 29 NICM patients without LBBB who had serial ECGs, sensitivity improved to 97% when all ECGs were considered. By comparison, human readers in a busy clinical environment had a sensitivity of 90% and specificity of 63%. A-ECG score trajectories demonstrated improvement, deterioration or no change in LVSD, which agreed with echocardiography, in 76% of cases (n = 25). Conclusion: A-ECG scoring detects LVSD due to NICM with high sensitivity and specificity. Serial A-ECG score trajectories also represent a method for inexpensively demonstrating changes in LVSD. A-ECG scoring may be of particular value in areas where echocardiography is unavailable, or as a gatekeeper for echocardiography. Full article
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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 9 | Viewed by 5077
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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Communication
Glucose Serum Concentrations and Cardiovascular Disease in Patients on the End Stage of Renal Disease without Diabetes Mellitus
by Vaia D. Raikou and Despina Kyriaki
J. Cardiovasc. Dev. Dis. 2015, 2(2), 66-75; https://doi.org/10.3390/jcdd2020066 - 24 Apr 2015
Viewed by 3655
Abstract
Background/Aim: It is still controversial whether tighter glycemic control is associated with better clinical outcomes in patients with kidney failure. We examined the association between glucose serum concentrations and cardiovascular disease in patients on the end stage of renal disease without diabetes [...] Read more.
Background/Aim: It is still controversial whether tighter glycemic control is associated with better clinical outcomes in patients with kidney failure. We examined the association between glucose serum concentrations and cardiovascular disease in patients on the end stage of renal disease without diabetes mellitus. Methods: We studied 76 patients on on-line hemodiafiltration. Cardiovascular disease was defined by the existence of coronary disease (CD). Arterial stiffness was measured as carotid-femoral pulse wave velocity (c-fPWV) and carotid augmentation index (AIx). The concentrations of beta2-microglobulin (β2M) and insulin were measured by radioimmunoassays and insulin resistance by HOMA-IR. We built a logistic-regression analysis to examine the role of glucose on cardiovascular disease after adjustment for the traditional and specific risk factors for dialysis patients. Results: Serum glucose was positively correlated with beta2M, insulin and HOMA-IR (r = 0.361, p = 0.002, r = 0.581, p = 0.001 and r = 0.753, p = 0.001 respectively). Logistic-regression analysis did not show significant impact of glucose concentrations on cardiovascular disease after adjustment for traditional and specific risk factors. Conclusions: The association between elevated glucose serum concentrations and represented by coronary syndrome cardiovascular disease in patients on the end stage of renal disease without diabetes mellitus was not found significant. Full article
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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 6 | Viewed by 6003
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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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 6463
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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