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Chronic kidney disease (CKD) has become a major public health problem in the USA and worldwide. A large majority of patients with CKD have mild to moderate disease and microalbuminuria. It has increasingly been noted that patients with CKD have a significantly higher risk of cardiovascular outcomes compared to patients with normal kidney function. Many studies have shown increased risk beginning at stage 3 CKD but risk has been elevated in patients with milder degrees of kidney dysfunction in some studies. This risk may be better predicted by the degree of albuminuria in the earlier stages of CKD. Data addressing interventions to improve outcomes in patients with mild to moderate CKD are scarce. In this paper, we examined data and post hoc analyses from the ORIGIN and ACCORD trials. Data indicate that intensive treatment of diabetes in patients with CKD actually may result in adverse outcomes. The mechanism by which CKD results in increased cardiovascular risk is not clear. Patients with CKD frequently have the traditional risk factors that cause cardiovascular disease and there are mechanisms that are unique to CKD that promote the development of cardiovascular disease. In this article, we describe in some detail traditional, newer and novel risk factors that play a role in the development of CKD and heart disease. [ABSTRACT FROM AUTHOR]

Conotruncal heart defects (CTDs) are among the most common and severe groups of congenital heart defects. Despite evidence of an inherited genetic contribution to CTDs, little is known about the specific genes that contribute to the development of CTDs. We performed gene-based genome-wide analyses using microarray-genotyped and imputed common and rare variants data from two large studies of CTDs in the United States. We performed two case-parent trio analyses (N = 640 and 317 trios), using an extension of the family-based multi-marker association test, and two case-control analyses (N = 482 and 406 patients and comparable numbers of controls), using a sequence kernel association test. We also undertook two meta-analyses to combine the results from the analyses that used the same approach (i.e. family-based or case-control). To our knowledge, these analyses are the first reported gene-based, genome-wide association studies of CTDs. Based on our findings, we propose eight CTD candidate genes (ARF5, EIF4E, KPNA1, MAP4K3, MBNL1, NCAPG, NDFUS1 and PSMG3). Four of these genes (ARF5, KPNA1, NDUFS1 and PSMG3) have not been previously associated with normal or abnormal heart development. In addition, our analyses provide additional evidence that genes involved in chromatin-modification and in ribonucleic acid splicing are associated with congenital heart defects. [ABSTRACT FROM AUTHOR]

Heart disease is the leading cause of death in the United States. Recent studies demonstrate that fetal programming of PKCε gene repression results in ischemia-sensitive phenotype in the heart. The present study tests the hypothesis that increased norepinephrine causes epigenetic repression of PKCε gene in the heart via Nox1-dependent reactive oxygen species (ROS) production. Prolonged norepinephrine treatment increased ROS production in fetal rat hearts and embryonic ventricular myocyte H9c2 cells via a selective increase in Nox1 expression. Norepinephrine-induced ROS resulted in an increase in PKCε promoter methylation at Egr-1 and Sp-1 binding sites, leading to PKCε gene repression. N-acetyl- cysteine, diphenyleneiodonium, and apocynin blocked norepinephrine-induced ROS production and the promoter methylation, and also restored PKCε mRNA and protein to control levels in vivo in fetal hearts and in vitro in embryonic myocyte cells. Accordingly, norepinephrine-induced ROS production, promoter methylation, and PKCε gene repression were completely abrogated by knockdown of Nox1 in cardiomyocytes. These findings provide evidence of a novel interaction between elevated norepinephrine and epigenetic repression of PKCε gene in the heart mediated by Nox1-dependent oxidative stress and suggest new insights of molecular mechanisms linking the heightened sympathetic activity to aberrant cardioprotection and increased ischemic vulnerability in the heart. [ABSTRACT FROM AUTHOR]

Heart disease is the leading cause of death in the United States and worldwide. Understanding the molecular mechanisms of cardiac development and regeneration will improve diagnostic and therapeutic interventions against heart disease. In this direction, zebrafish is an excellent model because several processes of zebrafish heart development are largely conserved in humans, and zebrafish has several advantages as a model organism. Zebrafish transcriptomic profiles undergo alterations during different stages of cardiac development and regeneration which are revealed by RNA-sequencing. ChIP-sequencing has detected genome-wide occupancy of histone post-translational modifications that epigenetically regulate gene expression and identified a locus with enhancer-like characteristics. ATAC-sequencing has identified active enhancers in cardiac progenitor cells during early developmental stages which overlap with occupancy of histone modifications of active transcription as determined by ChIP-sequencing. CRISPR-mediated editing of the zebrafish genome shows how chromatin modifiers and DNA-binding proteins regulate heart development, in association with crucial signaling pathways. Hence, more studies in this direction are essential to improve human health because they answer fundamental questions on cardiac development and regeneration, their differences, and why zebrafish hearts regenerate upon injury, unlike humans. This review focuses on some of the latest studies using state-of-the-art technology enabled by the elegant yet simple zebrafish. [ABSTRACT FROM AUTHOR]

Clinically relevant congenital heart disease affects 1% of all live births. It is the leading cause of birth defects–related death in the United States, claiming more than 6000 lives per year. Despite the many advances in our understanding of cardiac development, the fundamental etiology for the majority of cases of congenital heart disease (CHD) remains unknown. Although causal links have been established, including maternal diabetes, exposure to drugs, and genetic variants in a few genes, these, at best, explain a small fraction of cases. Elucidating the molecular basis of CHD presents several challenges. While CHD has an increased risk of recurrence within families, suggesting genes are at play, CHD occurs with variable expressivity. Several chromosomal abnormalities clearly associate with CHD; however, many children with these same chromosomal abnormalities have normal hearts. Thus, the etiology cannot be explained by simple Mendelian genetics. Abnormal cardiac development occurs through a process that is complex, possibly involving both genetic and environmental risk factors. Because the majority of cases occur without known cause, the molecular basis of CHD is an active and evolving discussion. [Copyright &y& Elsevier]

Cardiac Allograft Vasculopathy (CAV) is a leading cause of long-term graft dysfunction and loss after HT. Elevated plasma donor-derived cell-free DNA (dd-cfDNA) levels may predict de novo HLA Class I &/or II elaboration after HT. We queried whether dd-cfDNA levels may reflect new or progressive CAV development in the observational Surveillance HeartCare Outcomes Registry (SHORE). Over 1200 unique patients at 60 HT Centers across the United States were enrolled into surveillance by gene expression profiling (GEP; AlloMap®) and dd-cfDNA (AlloSure®) in concert with clinical, catheterization and pathologic data capture. Coronary assessments per angiography were classified as either "New" or "Progressive" while "Stable" or "None" comprised the comparison cohorts. We performed analysis by Cox Proportional Hazards Modeling and type III statistical testing with donor age and dd-cfDNA as covariates for development of CAV (p<0.05) We identified 195 unique HT recipients with dd-cfDNA data within the preceding 30-days of CAV assessment. There were 15 CAV events classified as either "New" or "Progressive" [TABLE]. Mean time from the last dd-cfDNA monitoring and CAV development was 6.07 days (9.95). Both dd-cfDNA (p=0.04) and donor-age (p=0.017) were significant covariates for CAV development. An association of donor-age (p=0.018) and a trend for dd-cfDNA plasma levels (p=0.079) with new onset / progressive CAV was demonstrated. Preliminary data from SHORE demonstrated the correlation of donor-age and CAV, while elevated dd-cfDNA plasma levels trended towards the development of new onset or progressive CAV after HT. Further data development that encompasses longer-term follow-up and standard CAV methods of assessment, should provide value in refining the impact of CAV on dd-cfDNA. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the most common birth defect worldwide and the number one killer of live-born infants in the United States. Heart development occurs early in embryogenesis and involves complex interactions between multiple cell populations, limiting the understanding and consequent treatment of CHD. Furthermore, genome sequencing has largely failed to predict or yield therapeutics for CHD. In addition to the underlying genome, epigenetics and mechanobiology both drive heart development. A growing body of evidence implicates the aberrant regulation of these two extra-genomic systems in the pathogenesis of CHD. In this review, we describe the stages of human heart development and the heart defects known to manifest at each stage. Next, we discuss the distinct and overlapping roles of epigenetics and mechanobiology in normal development and in the pathogenesis of CHD. Finally, we highlight recent advances in the identification of novel epigenetic biomarkers and environmental risk factors that may be useful for improved diagnosis and further elucidation of CHD etiology. [ABSTRACT FROM AUTHOR]

Backgrounds: Congenital heart diseases affect nearly 1% of neonates per year in the United States and are the leading cause of neonatal death. Despite a strong indication of genetic contribution to congenital heart diseases, the developmental processes and genetic components are poorly understood. From the large-scale forward genetic screen using inbred mice chemically mutagenized with ethyl-nitrosourea (ENU), a novel finding of endocytic trafficking gene mutations, including Lrp1, were recovered as causing congenital heart disease phenotypes. Endocytosis plays roles in modulating cell signaling by regulating the trafficking of the internalized endocytic vesicles to different endosomal compartments, some destined for fusion with lysosomes and degradation while others are recycled to the surface by recycling endosomes. Mutations in these genes causes a spectrum of congenital heart disease comprising of outflow tract abnormalities and alignment defects. Methods and Results: The LRP1 [line 1554(MGI 96828)] mutant mouse line recovered from a forward genetic screen results from a missense (C4232R) mutation in the region encoding the epidermal growth factor (EGF) repeat domain of LRP1. The mutants exhibit a spectrum of septation and outflow tract defects including endocardial cushion defects, double outlet of right ventricle with normal related great arteries as well as DORV with D-malposition of great arteries (Taussig-Bing anomalies). Mouse embryonic fibroblasts (MEF) from LRP1m/m mutants demonstrated decreased cell-surface expression and increased retention in the endosomes. Migration assay of MEF demonstrated decreased migration of LRP1m/m compared with control with normal Golgi orientation. The decreasing migration LRP1m/m also observed in the endocardial cushion tissue from E9.5-10.5 embryos. Different cell lineages crucial to cardiac development with tissue-specific genetic manipulations were used to define the roles of the LRP1 pathway in these three fields of cells during outflow tract development and septation. Cardiac neural crest cell (Wnt1-Cre) knockout of LRP1 recapitulate LRP1 m/m cardiac phenotypes as well as Nkx2.5/Tie2-cre double knockout of LRP1. RNA expression profile suggests Notch pathway and integrin pathway are associated with LRP1 during cardiac development. Conclusions: We provide the first evidence of endocytic vesicle trafficking pathway associated with the development of congenital heart diseases with malalignment/septation and outflow tract defects [ABSTRACT FROM AUTHOR]