He studies the identification and manipulation of age- and mutation-dependent modifiers of cardiac function, hierarchical modeling and imaging of contractile machinery, integrative analysis of striated muscle performan Research Areas: muscle development , genetics , myopathic processes , striated muscle biology , muscle function , myopathy , muscle physiology. Anthony Cammarato, Ph. The Cardiac Bioelectric Systems Laboratory research focuses on both the physiological and pathophysiological function of cardiac cells at a multicellular, syncytial level.
We use cell culture models in a manner akin to mathematical models in which elements of the model can be designed, synthesized or controlled. Our traditional approach consists of cultured, confluent monolayers of cardiac cells that number in the tens of thousands to a million. These cell monolayers can be engineered in terms of their tissue architecture, cell type, protein expression and microenvironment, and have been used to study clinically relevant phenomena in the heart that include electrical stimulation, electrical propagation, arrhythmia and cell therapy.
Research Areas: bioelectric systems , arrhythmia , cell therapy , cardiology. Leslie Tung, Ph. Biomedical Engineering. The Cardiology Bioengineering Laboratory, located in the Johns Hopkins Hospital, focuses on the applications of advanced imaging techniques for arrhythmia management. The primary limitation of current fluoroscopy-guided techniques for ablation of cardiac arrhythmia is the inability to visualize soft tissues and 3-dimensional anatomic relationships.
Implementation of alternative advanced modalities has the potential to improve complex ablation procedures by guiding catheter placement, visualizing abnormal scar tissue, reducing procedural time devoted to mapping, and eliminating patient and operator exposure to radiation. Menekhem M. Zviman, PhD is the laboratory manager.
Research Areas: magnetic resonance imaging , CPR models , cardiac mechanics , MRI-guided therapy , ischemic tachycardia , arrhythmia , cardiology , sudden cardiac death , cardiopulmonary resuscitation , computational modeling. Henry Halperin, M. Research Areas: cardiac imaging , cardiac computing tomography , coronary risk prediction , heart attack prevention. Armin Arbab-Zadeh, M. The Foster Lab uses the tools of protein biochemistry and proteomics to tackle fundamental problems in the fields of cardiac preconditioning and heart failure.
Protein networks are perturbed in heart disease in a manner that correlates only weakly with changes in mRNA transcripts.
Moreover, proteomic techniques afford the systematic assessment of post-translational modifications that regulate the activity of proteins responsible for every aspect of heart function from electrical excitation to contraction and metabolism. Understanding the status of protein networks in the diseased state is, therefore, key to discovering new therapies. Brian Foster, Ph. Research Areas: proteomics , protein biochemistry , heart failure , cardiology , cardiac preconditioning , cardiomyopathy.
Brian Foster, M. The main focus of Dr. Gilotra's research is understanding the pathophysiology and outcomes in inflammatory cardiomyopathies including myocarditis and sarcoidosis, as well as improvement of heart failure patient care through noninvasive hemodynamic monitoring and studying novel strategies to reduce heart failure hospitalizations. Additional investigations involve clinical research in advanced heart failure therapies including heart transplantation and mechanical circulatory support.
Research Areas: heart failure , cardiology , cardiomyopathy.
Nisha Gilotra, M. The Institute for Computational Medicine's mission is to develop quantitative approaches for understanding the mechanisms, diagnosis and treatment of human disease through biological systems modeling, computational anatomy, and bioinformatics. Our disease focus areas include breast cancer, brain disease and heart disease. Research Areas: breast cancer , systems biology , brain , biomedical engineering , cardiology , bioinformatics , computational anatomy. Raimond Winslow, Ph. View our phone directory or find a patient care location.
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All rights reserved. Skip Navigation. I Want To I Want to Find Research Faculty Enter the last name, specialty or keyword for your search below. Our observations therefore provide rationale in human tissue that the induction of EZH2 likely produces a phenotypic switch of ischemic cardiomyocytes, thereby resulting in colliquative myocytolysis. Altogether, these observations lead us to hypothesize that an EZH2-DNMT complex, a mechanism that requires additional exploration, may coordinate the ICM-associated differential methylation and downstream suppression of key metabolic enzymes and transcription factors such as KLF15 Fig.
Human ischemic heart failure presents a distinct DNA methylation signature associated with known changes from oxidative metabolism to anaerobic glycolysis. Bioinformatic analysis strongly supports the involvement of differential methylation mediated by EZH2 to coordinately decrease the expression of the transcription factor KLF15 and its function via response element methylation. In addition to the direct impact of differential CpG methylation on metabolic intermediate enzymes, our analysis also supports that gene suppression of transcription factor KLF15 occurs in ICM.
As an established regulator of myocardial fatty acid utilization, KLF15 is suppressed during fetal cardiac development and rapidly induced in the days following birth, during which time the fetal heart becomes reliant on oxidative metabolism as it is starved of a rich supply of placental nutrients [ 43 ]. Conversely, suppression of KLF15 has been shown to occur in heart failure, an expression pattern that closely reflects lipid utilization. Furthermore, KLF15 has been shown to negatively regulate adverse cardiac remodeling and hypertrophy in animal models [ 44 , 45 , 46 ].
In the current study we provide novel evidence suggesting that cardiac ischemia triggers its epigenetic regulation via promoter hypermethylation and EZH2-mediated suppression. Although further mechanistic experiments are required, we believe this observation highlights a convergence of multiple epigenetic mechanisms to control the transcriptional activity of KLF15 in response to cardiac ischemia. The gene expression changes in ICM relative to NICM have been previously studied using sizeable cohorts and microarray-based platforms.
Our analysis yields a consistent pattern of gene expression with that published by Kittleson et al. Although the current study demonstrates the importance of DNA methylation as a likely contributor to the gene expression changes that distinguish ischemic heart failure, key limitations must be considered when interpreting the results. Although we provide both histologic and in silico evidence that the effects of cellular heterogeneity are unlikely to confound our analysis, our whole-tissue analysis precludes us from defining cell-type specificity of the observed epigenetic changes.
Therefore, we cannot yet infer the differential effects of ischemia on DNA methylation in female heart failure patients. Future studies should consider the impact of ischemic heart failure on DNA methylation by sex, race, and other heart failure etiologies.
Lastly, the current study provides correlative evidence supporting the regulatory influence of promoter-associated DNA methylation on gene expression in human heart failure. Therefore, future mechanistic studies will explore the causative role of differential DNA methylation and EZH2 in heart failure pathogenesis and therapy. Our observations reveal a strong correlation between DNA methylation and the gene expression associated with the known metabolic shift that occurs in ischemic heart failure. Cardiac ischemia also correlates with induction of EZH2, an epigenetic regulator that may coordinate with differential DNA methylation to suppress KLF15 and other downstream metabolic gene targets Fig.
While these metabolic gene changes may initially protect the myocardium from energy collapse under ischemic conditions, it is possible that chronic exposure to ischemic stress potentiates the adverse cardiac structural and metabolic remodeling that defines heart failure. Lund LH.
Back to top Article Information. Wang, P. Recent advances in molecular and cellular biology have markedly changed our understanding of the heart, and this is having tremendous ramifications for the clinician. He has received awards at Duke University for both his teaching and mentoring of medical students. This study was approved by the ethics committee on human subject research at Huazhong University of Science and Technology and other appropriate local ethics committees on human subject research.
The inescapable heterogeneity of heart failure. J Card Fail. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. Marwick TH. The viable myocardium: epidemiology, detection, and clinical implications.
Beller GA. More evidence for the survival benefit of coronary revascularization versus medical therapy in patients with ischemic cardiomyopathy and hibernating myocardium. Circ Cardiovasc Imaging. A systematic study of a myocardial lesion: colliquative myocytolysis. Int J Cardiol. Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann N Y Acad Sci.
Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. Metabolic origins of heart failure. Chronic hypoxia during gestation causes epigenetic repression of the estrogen receptor-alpha gene in ovine uterine arteries via heightened promoter methylation. Epigenetic reprogramming in cancer. Shlomi T, Rabinowitz JD. Metabolism: cancer mistunes methylation.
Nat Chem Biol. Laird PW, Jaenisch R. The role of DNA methylation in cancer genetic and epigenetics. Annu Rev Genet. Regional variation in mRNA transcript abundance within the ventricular wall. J Mol Cell Cardiol. Cardiac ventricular chambers are epigenetically distinguishable. Cell Cycle. Genome Biol. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells.
Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans. Basic Res Cardiol. Glucose transporter 4-deficient hearts develop maladaptive hypertrophy in response to physiological or pathological stresses. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinforma. Consortium EP. Mouse cardiac surgery: comprehensive techniques for the generation of mouse models of human diseases and their application for genomic studies. Physiol Genom. Panminerva Med.
www.newbeingkings.com/includes/zithromax-azithromycin-e-coronavirus.php Activation of the cardiac interleukin-6 system in advanced heart failure. Eur J Heart Fail. PLoS Genet. On the presence and role of human gene-body DNA methylation. Bird AP. CpG-rich islands and the function of DNA methylation. WebGestalt a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit. Nucleic Acids Res. Reactome pathway analysis: a high-performance in-memory approach. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. Quantifying similarity between motifs.
Contemporary definitions and classification of the cardiomyopathies: an American heart association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Warburg O.
On the origin of cancer cells. The abundance of metabolites related to protein methylation correlates with the metastatic capacity of human melanoma xenografts. Sci Adv. Sci Rep. Hirai H, Kikyo N. Inhibitors of suppressive histone modification promote direct reprogramming of fibroblasts to cardiomyocyte-like cells. Cardiovasc Res. Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism.
J Biol Chem. PPAR Res. Repression of cardiac hypertrophy by KLF underlying mechanisms and therapeutic implications. KLF15 is an essential negative regulatory factor for the cardiac remodeling response to pressure overload. Gene expression analysis of ischemic and nonischemic cardiomyopathy: shared and distinct genes in the development of heart failure. RNA-Seq identifies novel myocardial gene expression signatures of heart failure.
Download references. We thank Dr. Malay Basu and Vincent A. Laufer, for training MEP in the bioinformatics-based concepts used in this study. Correspondence to Adam R. Informed consent was granted to the UAB Cardiovascular Tissue Bank for the procurement of left ventricular assist device LVAD core biopsies and de-identified patient health history with demographics were obtained to maintain confidentiality. Reprints and Permissions. Epigenomics Endocrinology Frontiers in Endocrinology Advanced search. Skip to main content. Abstract Ischemic cardiomyopathy ICM is the clinical endpoint of coronary heart disease and a leading cause of heart failure.
Introduction Coronary heart disease CHD is the leading cause of death and disability in developed countries. Materials and methods Human left ventricular cardiac samples Adult heart failure patients admitted to the University of Alabama at Birmingham University Hospital for LVAD implantation due to end-stage heart failure were considered for the study.
Full size image. Histologic and transcriptional analysis for cellular heterogeneity Because tissue and cellular composition are shown to influence differential gene expression within RNA sequencing data [ 22 ], we inspected the biopsies in a blinded fashion based on histopathologic evidence of ischemia. Discussion Despite advances in both preventive measures and interventional approaches, ischemic heart disease remains the most common cause of heart failure, a terminal disease that affects nearly 6 million individuals in the United States.
Epigenetic reprogramming of cardiac metabolism Although nutrient-dependent changes in cardiac metabolism have been known to occur for over 50 years via so-called Randle Cycle [ 37 ], the specific molecular cues that both maintain and switch its substrate preference remain unknown. References 1. Article Google Scholar 2.
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