Publications
228 results found
Barbato E, Barton PJ, Bartunek J, et al., 2015, Review and Updates in Regenerative and Personalized Medicine, Preclinical Animal Models, and Clinical Care in Cardiovascular Medicine, Journal of Cardiovascular Translational Research, Vol: 8, Pages: 466-474, ISSN: 1937-5395
The goal of this paper is to provide an updated review for scientists and clinicians on the major areas in cardiovascular medicine published in the Journal. Leading topics in regenerative and personalized medicine are presented along with a critical overview of the field. New standards in large preclinical animal models of pulmonary hypertension and left bundle branch block are highlighted. Finally, clinical care in the areas of atherosclerosis, the aortic valve, platelet biology, and myocarditis is discussed as well as autonomic modulation therapies.
Buyandelger B, Mansfield C, Kostin S, et al., 2015, ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure., Circulation. Cardiovascular Genetics, Vol: 8, Pages: 643-652, ISSN: 1942-3268
BACKGROUND: -Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects. METHODS AND RESULTS: -We used cysteine and glycine-rich protein 3 (CSRP3), a known cardiomyopathy gene, in a yeast two-hybrid screen and identified zinc finger and BTB domain containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner. CONCLUSIONS: -We revealed new functions for ZBTB17 in the heart, a transcription factor which may play a role as a novel cardiomyopathy gene.
Fletcher ME, Boshier PR, Wakabayashi K, et al., 2015, Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 308, Pages: L1274-L1285, ISSN: 1040-0605
Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD+/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.
Rea G, Petyrka J, Vieira M, et al., 2015, THE GENETIC SIGNATURE IN ISCHAEMIC HEART DISEASE WITH MYOCARDIAL INFARCTION (MI) AND SIGNIFICANT LEFT VENTRICULAR (LV) DYSFUNCTION, British-Cardiac-Society (BCS) Annual Conference on Hearts and Genes, Publisher: BMJ PUBLISHING GROUP, Pages: A97-A97, ISSN: 1355-6037
Sanoudou D, Kolokathis F, Arvanitis D, et al., 2015, Genetic modifiers to the PLN L39X mutation in a patient with DCM and sustained ventricular tachycardia?, Global Cardiology Science and Practice, Vol: 2015, ISSN: 2305-7823
Garnier S, Hengstenberg C, Lamblin N, et al., 2015, Involvement of BAG3 and HSPB7 loci in various etiologies of systolic heart failure: results of a European collaboration assembling more than 2000 patients, International Journal of Cardiology, Vol: 189, Pages: 105-107, ISSN: 1874-1754
Roberts AM, Ware JS, Herman DS, et al., 2015, What Happens When Titins Are Trimmed?, SCIENCE TRANSLATIONAL MEDICINE, Vol: 7, ISSN: 1946-6234
Roberts AM, Ware JS, Herman DS, et al., 2015, Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease, Science Translational Medicine, Vol: 7, Pages: 270ra6-270ra6, ISSN: 1946-6234
The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.
Lee R, Xu B, Rame JE, et al., 2014, Regulated Inositol‐Requiring Protein 1‐Dependent Decay as a Mechanism of Corin RNA and Protein Deficiency in Advanced Human Systolic Heart Failure, Journal of the American Heart Association, Vol: 3, ISSN: 2047-9980
BACKGROUND: The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide pro‐hormones into biologically active, carboxyl‐terminal fragments. Natriuretic peptide pro‐peptide processing is accomplished by corin, a transmembrane serine protease expressed by cardiomyocytes. Brain natriuretic peptide (BNP) processing is inadequate in advanced heart failure and is independently associated with adverse outcomes; however, the molecular mechanisms causing impaired BNP processing are not understood. We hypothesized that the development of endoplasmic reticulum stress in cardiomyocytes in advanced heart failure triggers inositol‐requiring protein 1 (IRE1)‐dependent corin mRNA decay, which would favor a molecular substrate favoring impaired natriuretic peptide pro‐peptide processing. METHODS AND RESULTS: Two independent samples of hearts obtained from patients with advanced heart failure at transplant demonstrated that corin RNA was reduced as Atrial natriuretic peptide (ANP)/BNP RNA increased. Increases in spliced X‐box protein 1, a marker for IRE1‐endoribonuclease activity, were associated with decreased corin RNA. Moreover, ≈50% of the hearts demonstrated significant reductions in corin RNA and protein as compared to the nonfailing control sample. In vitro experiments demonstrated that induction of endoplasmic reticulum stress in cultured cardiomyocytes with thapsigargin activated IRE1's endoribonuclease activity and time‐dependent reductions in corin mRNA. In HL‐1 cells, overexpression of IRE1 activated IRE1 endoribonuclease activity and caused corin mRNA decay, whereas IRE1‐RNA interference with shRNA attenuated corin mRNA decay after induction of endoplasmic reticulum stress with thapsigargin. Pre‐treatment of cells with Actinomycin D to inhibit transcription did not alter the magnitude or time course of thapsigargin‐induced corin mRNA decline, supporting the hypothesis that this was the result of IRE1‐medi
Maatz H, Jens M, Liss M, et al., 2014, RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-rnRNA processing, JOURNAL OF CLINICAL INVESTIGATION, Vol: 124, Pages: 3419-3430, ISSN: 0021-9738
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- Citations: 135
Adhikari N, Guan W, Capaldo B, et al., 2014, Identification of a New Target of miR-16, Vacuolar Protein Sorting 4a, PLoS One, Vol: 9, Pages: 1-10, ISSN: 1932-6203
RationaleThe rationale was to utilize a bioinformatics approach to identify miRNA binding sites in genes with single nucleotide mutations (SNPs) to discover pathways in heart failure (HF).ObjectiveThe objective was to focus on the genes containing miRNA binding sites with miRNAs that were significantly altered in end-stage HF and in response to a left ventricular assist device (LVAD).Methods and ResultsBEDTools v2.14.3 was used to discriminate SNPs within predicted 3′UTR miRNA binding sites. A member of the miR-15/107 family, miR-16, was decreased in the circulation of end-stage HF patients and increased in response to a LVAD (p<0.001). MiR-16 decreased Vacuolar Protein Sorting 4a (VPS4a) expression in HEK 293T cells (p<0.01). The SNP rs16958754 was identified in the miR-15/107 family binding site of VPS4a which abolished direct binding of miR-16 to the 3′UTR of VPS4a (p<0.05). VPS4a was increased in the circulation of end-stage HF patients (p<0.001), and led to a decrease in the number of HEK 293T cells in vitro (p<0.001).ConclusionsWe provide evidence that miR-16 decreases in the circulation of end-stage HF patients and increases with a LVAD. Modeling studies suggest that miR-16 binds to and decreases expression of VPS4a. Overexpression of VPS4a decreases cell number. Together, these experiments suggest that miR-16 and VPS4a expression are altered in end-stage HF and in response to unloading with a LVAD. This signaling pathway may lead to reduced circulating cell number in HF.
Barbato E, Lara-Pezzi E, Stolen C, et al., 2014, Advances in Induced Pluripotent Stem Cells, Genomics, Biomarkers, and Antiplatelet Therapy Highlights of the Year in JCTR 2013, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 7, Pages: 518-525, ISSN: 1937-5387
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- Citations: 3
Smolenski RT, Rybakowska I, Turyn J, et al., 2014, AMP deaminase 1 gene polymorphism and heart disease-A genetic association that highlights new treatment, Cardiovascular Drugs and Therapy, Vol: 28, Pages: 183-189, ISSN: 0920-3206
Nucleotide metabolism and signalling is directly linked to myocardial function. Therefore analysis how diversity of genes coding nucleotide metabolism related proteins affects clinical progress of heart disease could provide valuable information for development of new treatments. Several studies identified that polymorphism of AMP deaminase 1 gene (AMPD1), in particular the common C34T variant of this gene was found to benefit patients with heart failure and ischemic heart disease. However, these findings were inconsistent in subsequent studies. This prompted our detailed analysis of heart transplant recipients that revealed diverse effect: improved early postoperative cardiac function associated with C34T mutation in donors, but worse 1-year survival. Our other studies on the metabolic impact of AMPD1 C34T mutation revealed decrease in AMPD activity, increased production of adenosine and de-inhibition of AMP regulated protein kinase. Thus, genetic, clinical and biochemical studies revealed that while long term attenuation of AMPD activity could be deleterious, transient inhibition of AMPD activity before acute cardiac injury is protective. We suggest therefore that pharmacological inhibition of AMP deaminase before transient ischemic event such as during ischemic heart disease or cardiac surgery could provide therapeutic benefit.
Gatto A, Torroja-Fungairino C, Mazzarotto F, et al., 2014, FineSplice, enhanced splice junction detection and quantification: a novel pipeline based on the assessment of diverse RNA-Seq alignment solutions, Nucleic Acids Research, Vol: 42, Pages: 1-11, ISSN: 0305-1048
Alternative splicing is the main mechanism governing protein diversity. The recent developments in RNA-Seq technology have enabled the study of the global impact and regulation of this biological process. However, the lack of standardized protocols constitutes a major bottleneck in the analysis of alternative splicing. This is particularly important for the identification of exon–exon junctions, which is a critical step in any analysis workflow. Here we performed a systematic benchmarking of alignment tools to dissect the impact of design and method on the mapping, detection and quantification of splice junctions from multi-exon reads. Accordingly, we devised a novel pipeline based on TopHat2 combined with a splice junction detection algorithm, which we have named FineSplice. FineSplice allows effective elimination of spurious junction hits arising from artefactual alignments, achieving up to 99% precision in both real and simulated data sets and yielding superior F1 scores under most tested conditions. The proposed strategy conjugates an efficient mapping solution with a semi-supervised anomaly detection scheme to filter out false positives and allows reliable estimation of expressed junctions from the alignment output. Ultimately this provides more accurate information to identify meaningful splicing patterns. FineSplice is freely available at https://sourceforge.net/p/finesplice/.
Burton PBJ, Yacoub MH, Barton PJR, 2014, Rapamycin (sirolimus) inhibits heart cell growth in vitro, PEDIATRIC CARDIOLOGY, Vol: 19, Pages: 468-470, ISSN: 0172-0643
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- Citations: 8
Baksi AJ, Roberts AM, Ware JS, et al., 2014, Titin: a phenotype-genotype descriptive comparison of dilated cardiomyopathy, ISSN: 1097-6647
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- Citations: 2
Rybakowska I, Romaszko P, Zabielska M, et al., 2014, EFFECT OF AMP-DEAMINASE 3 KNOCK-OUT IN MICE ON ENZYME ACTIVITY IN HEART AND OTHER ORGANS, NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, Vol: 33, Pages: 319-322, ISSN: 1525-7770
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- Citations: 2
Arndt A-K, Schafer S, Drenckhahn J-D, et al., 2013, Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of <i>PRDM16</i> as a Cause of Cardiomyopathy, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 93, Pages: 67-77, ISSN: 0002-9297
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- Citations: 117
Li X, Buckton AJ, Wilkinson SL, et al., 2013, Towards Clinical Molecular Diagnosis of Inherited Cardiac Conditions: A Comparison of Bench-Top Genome DNA Sequencers, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 98
Zhou W, Suntharalingam K, Brand NJ, et al., 2013, Possible Regulatory Roles of Promoter G-Quadruplexes in Cardiac Function-Related Genes - Human TnIc as a Model, PLOS One, Vol: 8, ISSN: 1932-6203
G-quadruplexes (G4s) are four-stranded DNA secondary structures, which are involved in a diverse range of biological processes. Although the anti-cancer potential of G4s in oncogene promoters has been thoroughly investigated, the functions of promoter G4s in non-cancer-related genes are not well understood. We have explored the possible regulatory roles of promoter G4s in cardiac function-related genes using both computational and a wide range of experimental approaches. According to our bioinformatics results, it was found that potential G4-forming sequences are particularly enriched in the transcription regulatory regions (TRRs) of cardiac function-related genes. Subsequently, the promoter of human cardiac troponin I (TnIc) was chosen as a model, and G4s found in this region were subjected to biophysical characterisations. The chromosome 19 specific minisatellite G4 sequence (MNSG4) and near transcription start site (TSS) G4 sequence (−80 G4) adopt anti-parallel and parallel structures respectively in 100 mM KCl, with stabilities comparable to those of oncogene G4s. It was also found that TnIc G4s act cooperatively as enhancers in gene expression regulation in HEK293 cells, when stabilised by a synthetic G4-binding ligand. This study provides the first evidence of the biological significance of promoter G4s in cardiac function-related genes. The feasibility of using a single ligand to target multiple G4s in a particular gene has also been discussed.
Panse KD, Felkin LE, Lopez-Olaneta MM, et al., 2012, Follistatin-Like 3 Mediates Paracrine Fibroblast Activation by Cardiomyocytes, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 5, Pages: 814-826, ISSN: 1937-5387
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- Citations: 31
Herman D, Lam L, Taylor M, et al., 2012, Truncations of Titin Causing DilatedCardiomyopathy, New England Journal of Medicine, Vol: 366, Pages: 619-628
McDermott-Roe C, Ye J, Ahmed R, et al., 2011, Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function, Nature, Vol: 478, Pages: 114-118
Knoell R, Linke WA, Zou P, et al., 2011, Telethonin Deficiency Is Associated With Maladaptation to Biomechanical Stress in the Mammalian Heart, CIRCULATION RESEARCH, Vol: 109, Pages: 758-U153, ISSN: 0009-7330
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- Citations: 64
Felkin LE, Narita T, Germack R, et al., 2011, Calcineurin splicing variant calcineurin Aβ1 improves cardiac function after myocardial infarction without inducing hypertrophy., Circulation, Vol: 123, Pages: 2838-2847
Calcineurin is a calcium-regulated phosphatase that plays a major role in cardiac hypertrophy. We previously described that alternative splicing of the calcineurin Aβ (CnAβ) gene generates the CnAβ1 isoform, with a unique C-terminal region that is different from the autoinhibitory domain present in all other CnA isoforms. In skeletal muscle, CnAβ1 is necessary for myoblast proliferation and stimulates regeneration, reducing fibrosis and accelerating the resolution of inflammation. Its role in the heart is currently unknown.
Taegtmeyer AB, Breen JB, Smith J, et al., 2011, Effect of ABCB1 Genotype on Pre- and Post-Cardiac Transplantation Plasma Lipid Concentrations, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 4, Pages: 304-312, ISSN: 1937-5387
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- Citations: 13
Felkin LE, Lara-Pezzi EA, Hall JL, et al., 2011, Reverse Remodelling and Recovery from Heart Failure Are Associated with Complex Patterns of Gene Expression, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 4, Pages: 321-331, ISSN: 1937-5387
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- Citations: 24
Villard E, Perret C, Gary F, et al., 2011, A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy, EUROPEAN HEART JOURNAL, Vol: 32, Pages: 1065-1076, ISSN: 0195-668X
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- Citations: 240
Segura AM, Barton P, George R, et al., 2011, Correlation of Fibrosis and Hypertrophy with Myocardial Improvement during Left Ventricular Assist Device (LVAD) Support, 31st Annual Meeting and Scientific Sessions on International-Society-for-Heart-and-Lung-Transplantation, Publisher: ELSEVIER SCIENCE INC, Pages: S77-S77, ISSN: 1053-2498
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- Citations: 1
Hall JL, Fermin DR, Birks EJ, et al., 2011, Clinical, Molecular, and Genomic Changes in Response to a Left Ventricular Assist Device, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 57, Pages: 641-652, ISSN: 0735-1097
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- Citations: 91
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