Terrence X O'Brien

Publications of Terrence X O'Brien

• Iron metabolism, anemia, and heart failure.

  Authors: Terrence X O'Brien

  Journal of the American College of Cardiology. 09/2011; 58(12):1252-3.

• Evaluation of heavily calcified vessels with coronary CT angiography: comparison of iterative and filtered back projection image reconstruction.

  Authors: Matthias Renker, John W Nance, U Joseph Schoepf, Terrence X O'Brien, Peter L Zwerner, Mathias Meyer, J Matthias Kerl, Ralf W Bauer, Christian Fink, Thomas J Vogl, Thomas Henzler

  Radiology. 06/2011; 260(2):390-9.

  To prospectively compare traditional filtered back projection (FBP) and iterative image reconstruction for the evaluation of heavily calcified arteries with coronary computed tomography (CT)To prospectively compare traditional filtered back projection (FBP) and iterative image reconstruction for the evaluation of heavily calcified arteries with coronary computed tomography (CT) angiography. The study had institutional review board approval and was HIPAA compliant. Written informed consent was obtained from all patients. Fifty-five consecutive patients (35 men, 20 women; mean age, 58 years ± 12 [standard deviation]) with Agatston scores of at least 400 underwent coronary CT angiography and cardiac catheterization. Image data were reconstructed with both FBP and iterative reconstruction techniques with corresponding cardiac algorithms. Image noise and subjective image quality were compared. To objectively assess the effect of FBP and iterative reconstruction on blooming artifacts, volumes of circumscribed calcifications were measured with dedicated volume analysis software. FBP and iterative reconstruction series were independently evaluated for coronary artery stenosis greater than 50%, and their diagnostic accuracy was compared, with cardiac catheterization as the reference standard. Statistical analyses included paired t tests, Kruskal-Wallis analysis of variance, and a modified McNemar test. Image noise measured significantly lower (P = .011-.035) with iterative reconstruction instead of FBP. Image quality was rated significantly higher (P = .031 and .042) with iterative reconstruction series than with FBP. Calcification volumes measured significantly lower (P = .019 and .026) with iterative reconstruction (44.3 mm(3) ± 64.7 and 46.2 mm(3) ± 68.8) than with FBP (54.5 mm(3) ± 69.5 and 56.3 mm(3) ± 72.5). Iterative reconstruction significantly improved some measures of per-segment diagnostic accuracy of coronary CT angiography for the detection of significant stenosis compared with FBP (accuracy: 95.9% vs 91.8%, P = .0001; specificity: 95.8% vs 91.2%, P = .0001; positive predictive value: 76.9% vs 61.1%, P = .0001). Iterative reconstruction reduces image noise and blooming artifacts from calcifications, leading to improved diagnostic accuracy of coronary CT angiography in patients with heavily calcified coronary arteries.

• Coronary CT angiography: image quality, diagnostic accuracy, and potential for radiation dose reduction using a novel iterative image reconstruction technique-comparison with traditional filtered back projection.

  Authors: Antonio Moscariello, Richard A P Takx, U Joseph Schoepf, Matthias Renker, Peter L Zwerner, Terrence X O'Brien, Thomas Allmendinger, Sebastian Vogt, Bernhard Schmidt, Giancarlo Savino, Christian Fink, Lorenzo Bonomo, Thomas Henzler

  European radiology. 05/2011; 21(10):2130-8.

  To compare image noise, image quality and diagnostic accuracy of coronary CT angiography (cCTA) using a novel iterative reconstruction algorithm versus traditional filtered back projection (FBP) andTo compare image noise, image quality and diagnostic accuracy of coronary CT angiography (cCTA) using a novel iterative reconstruction algorithm versus traditional filtered back projection (FBP) and to estimate the potential for radiation dose savings. Sixty five consecutive patients (48 men; 59.3 ± 7.7 years) prospectively underwent cCTA and coronary catheter angiography (CCA). Full radiation dose data, using all projections, were reconstructed with FBP. To simulate image acquisition at half the radiation dose, 50% of the projections were discarded from the raw data. The resulting half-dose data were reconstructed with sinogram-affirmed iterative reconstruction (SAFIRE). Full-dose FBP and half-dose iterative reconstructions were compared with regard to image noise and image quality, and their respective accuracy for stenosis detection was compared against CCA. Compared with full-dose FBP, half-dose iterative reconstructions showed significantly (p = 0.001 - p = 0.025) lower image noise and slightly higher image quality. Iterative reconstruction improved the accuracy of stenosis detection compared with FBP (per-patient: accuracy 96.9% vs. 93.8%, sensitivity 100% vs. 100%, specificity 94.6% vs. 89.2%, NPV 100% vs. 100%, PPV 93.3% vs. 87.5%). Iterative reconstruction significantly reduces image noise without loss of diagnostic information and holds the potential for substantial radiation dose reduction from cCTA.

• Takotsubo cardiomyopathy in a patient with previously undiagnosed hypertrophic cardiomyopathy with obstruction.

  Authors: William W Brabham, Geoffrey F Lewis, David D Bonnema, Christopher D Nielsen, Terrence X O'Brien

  Cardiovascular revascularization medicine : including molecular interventions. 10/2010; 12(1):70.e1-5.

  Takotsubo cardiomyopathy (TCM) is usually characterized by left ventricular anteroapical dysfunction in the absence of significant coronary disease commonly precipitated by an emotional or stressfulTakotsubo cardiomyopathy (TCM) is usually characterized by left ventricular anteroapical dysfunction in the absence of significant coronary disease commonly precipitated by an emotional or stressful trigger. Hypertrophic cardiomyopathy (HCM) is usually diagnosed on the basis of symptoms, family history, echocardiography, or by the presence of a characteristic murmur. We report a unique case of TCM occurring in a patient with previously undiagnosed HCM with left ventricular outflow tract (LVOT) obstruction who presented with an acute coronary syndrome and ultimately underwent successful alcohol septal ablation. The potential pathophysiologic correlations are discussed.

• Dual-source computed tomography assessment of malfunctioning mechanical prosthetic valve.

  Authors: Gorka Bastarrika, William W Brabham, Terrence X O'Brien, Philip Costello, U Joseph Schoepf

  The Annals of thoracic surgery. 06/2009; 87(5):e50.

• Differentiation of cardiac Purkinje fibers requires precise spatiotemporal regulation of Nkx2-5 expression.

  Authors: Brett S Harris, Laura Spruill, Angela M Edmonson, Mary S Rackley, D Woodrow Benson, Terrence X O'Brien, Robert G Gourdie

  Developmental dynamics : an official publication of the American Association of Anatomists. 02/2006; 235(1):38-49.

  Nkx2-5 gene mutations cause cardiac abnormalities, including deficits of function in the atrioventricular conduction system (AVCS). In the chick, Nkx2-5 is elevated in Purkinje fiber AVCS cellsNkx2-5 gene mutations cause cardiac abnormalities, including deficits of function in the atrioventricular conduction system (AVCS). In the chick, Nkx2-5 is elevated in Purkinje fiber AVCS cells relative to working cardiomyocytes. Here, we show that Nkx2-5 expression rises to a peak as Purkinje fibers progressively differentiate. To disrupt this pattern, we overexpressed Nkx2-5 from embryonic day 10, as Purkinje fibers are recruited within developing chick hearts. Overexpression of Nkx2-5 caused inhibition of slow tonic myosin heavy chain protein (sMHC), a late Purkinje fiber marker but did not affect Cx40 levels. Working cardiomyocytes overexpressing Nkx2-5 in these hearts ectopically up-regulated Cx40 but not sMHC. Isolated embryonic cardiomyocytes overexpressing Nkx2-5 also displayed increased Cx40 and suppressed sMHC. By contrast, overexpression of a human NKX2-5 mutant did not effect these markers in vivo or in vitro, suggesting one possible mechanism for clinical phenotypes. We conclude that a prerequisite for normal Purkinje fiber maturation is precise regulation of Nkx2-5 levels.

• Atrioventricular conduction system and transcription factors Nkx2.5 and Msx2.

  Authors: Brett S Harris, Robert G Gourdie, Terrence X O'Brien

  Journal of cardiovascular electrophysiology. 02/2005; 16(1):86-7.

• Function follows form: cardiac conduction system defects in Nkx2-5 mutation.

  Authors: Patrick Y Jay, Brett S Harris, Antje Buerger, Olga Rozhitskaya, Colin T Maguire, Laura A Barbosky, Ellen McCusty, Charles I Berul, Terrence X O'Brien, Robert G Gourdie, Seigo Izumo

  The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology. 11/2004; 280(2):966-72.

  Mutations of Nkx2-5 cause congenital heart disease and atrioventricular block in man. The altered expression of an electrophysiologic protein regulated by Nkx2-5 was originally presumed to cause theMutations of Nkx2-5 cause congenital heart disease and atrioventricular block in man. The altered expression of an electrophysiologic protein regulated by Nkx2-5 was originally presumed to cause the conduction defect, but when no such protein was found, an alternative hypothesis was considered. In pediatric patients, the association of certain cardiac malformations with congenital atrioventricular block suggests that errors in specific developmental pathways could cause both an anatomic and a physiologic defect. We therefore hypothesized that Nkx2-5 insufficiency perturbs the conduction system during development, which in turn manifests as a postnatal conduction defect. Experimental results from Nkx2-5 knockout mouse models support the developmental hypothesis. Hypoplasia of the atrioventricular node, His bundle, and Purkinje system can explain in whole or in part specific conduction and electrophysiologic defects present in Nkx2-5 haploinsufficiency.

• Transcriptional regulation of cardiac conduction system development: 2004 FASEB cardiac conduction system minimeeting, Washington, DC.

  Authors: Brett S Harris, Patrick Y Jay, Mary S Rackley, Seigo Izumo, Terrence X O'Brien, Robert G Gourdie

  The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology. 11/2004; 280(2):1036-45.

  The development of the complex network of specialized cells that form the atrioventricular conduction system (AVCS) during cardiac morphogenesis occurs by progressive recruitment within a multipotentThe development of the complex network of specialized cells that form the atrioventricular conduction system (AVCS) during cardiac morphogenesis occurs by progressive recruitment within a multipotent cardiomyogenic lineage. Understanding the molecular control of this developmental process has been the focus of recent research. Transcription factors representative of multiple subfamilies have been identified and include members of zinc-finger subfamilies (GATA4, GATA6 HF-1b), skeletal muscle transcription factors (MyoD), T-box genes (Tbx5), and also homeodomain transcription factors (Msx2 and Nkx2.5). Mutations in some of these transcription factors cause congenital heart disease and are associated with cardiac abnormalities, including deficits within the AVCS. Mouse models that closely phenocopy known human heart disease provide powerful tools for the study of molecular effectors of AVCS development. Indeed, investigations of the Nkx2.5 haploinsufficient mouse have shown that peripheral Purkinje fibers are significantly underrepresented. This piece of data corroborates our previous work showing in chick, mouse, and humans that Nkx2.5 is elevated in the differentiating AVCS relative to adjacent working ventricular myocardial tissues. Using the chick embryo as a model, we show that this elevation of Nkx2.5 is transient in the network of conduction cells comprising the peripheral Purkinje fiber system. Functional studies using defective adenoviral constructs, which disrupt the normal variation in level of this gene, result in perturbations of Purkinje fiber phenotype. Thus, the precise spatiotemporal regulation of Nkx2.5 levels during development may be required for the progressive emergence of gene expression patterns specific to differentiated Purkinje fiber cells.

• Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system.

  Authors: Patrick Y Jay, Brett S Harris, Colin T Maguire, Antje Buerger, Hiroko Wakimoto, Makoto Tanaka, Sabina Kupershmidt, Dan M Roden, Thomas M Schultheiss, Terrence X O'Brien, Robert G Gourdie, Charles I Berul, Seigo Izumo

  The Journal of clinical investigation. 05/2004; 113(8):1130-7.

  Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause atrioventricular conduction defects in humans by unknown mechanisms. We show in KO mice that the number of cells in the cardiacHeterozygous mutations of the cardiac transcription factor Nkx2-5 cause atrioventricular conduction defects in humans by unknown mechanisms. We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage. Null mutant embryos appear to lack the primordium of the atrioventricular node. In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells. In addition, an entire population of connexin40(-)/connexin45(+) cells is missing in the atrioventricular node of Nkx2-5 heterozygous KO mice. Specific functional defects associated with Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system. Surprisingly, the cellular expression of connexin40, the major gap junction isoform of Purkinje fibers and a putative Nkx2-5 target, is unaffected, consistent with normal conduction times through the His-Purkinje system measured in vivo. Postnatal conduction defects in Nkx2-5 mutation may result at least in part from a defect in the genetic program that governs the recruitment or retention of embryonic cardiac myocytes in the conduction system.

• Development of the cardiac pacemaking and conduction system.

  Authors: Robert G Gourdie, Brett S Harris, Jaqueline Bond, Charles Justus, Kenneth W Hewett, Terrence X O'Brien, Robert P Thompson, David Sedmera

  Birth defects research. Part C, Embryo today : reviews. 03/2003; 69(1):46-57.

  The heartbeat is initiated and coordinated by a heterogeneous set of tissues, collectively referred to as the pacemaking and conduction system (PCS). While the structural and physiological propertiesThe heartbeat is initiated and coordinated by a heterogeneous set of tissues, collectively referred to as the pacemaking and conduction system (PCS). While the structural and physiological properties of these specialized tissues has been studied for more than a century, distinct new insights have emerged in recent years. The tools of molecular biology and the lessons of modern embryology are beginning to uncover the mechanisms governing induction, patterning and developmental integration of the PCS. In particular, significant advances have been made in understanding the developmental biology of the fast conduction network in the ventricles--the His-Purkinje system. Although this progress has largely been made by using animal models such as the chick and mouse, the insights gained may help explain cardiac disease in humans, as well as lead to new treatment strategies.

• His-Purkinje lineages and development.

  Authors: Robert G Gourdie, Brett S Harris, Jacqueline Bond, Angela M Edmondson, Gang Cheng, David Sedmera, Terrence X O'Brien, Takashi Mikawa, Robert P Thompson

  Novartis Foundation symposium. 02/2003; 250:110-22; discussion 122-4, 276-9.

  The heartbeat is initiated and coordinated by a multi-component set of specialized muscle tissues collectively referred to as the pacemaking and conduction system. Over the last few years, impetusThe heartbeat is initiated and coordinated by a multi-component set of specialized muscle tissues collectively referred to as the pacemaking and conduction system. Over the last few years, impetus has gathered into unravelling the cellular and molecular processes that regulate differentiation and integration of this essential cardiac network. One focus of our collective work has been the developmental history of cells comprising His-Purkinje tissues of the conduction system. This interest in part arose from studies of the expression of connexins in periarterial Purkinje fibres of the chick heart. Using lineage-tracing strategies, including those based on replication-defective retroviruses and adenoviruses, it has been shown that conduction cells are derived from multipotent, cardiomyogenic progenitors in the tubular heart. Moreover, heterogeneity within myocardial clones has indicated that the elaboration of the conduction system in the chick embryo occurs by progressive, localized recruitment from within this pool of cardiomyogenic cells. Cell birth dating has revealed that inductive conscription of cells to central elements of the conduction system (e.g. the His bundle) precedes recruitment to the peripheral components of the network (i.e. subendocardial and periarterial Purkinje fibres). Birth dating studies in rodents suggest an analogous recruitment process is occurring in this species. In addition to summarizing earlier work, this chapter provides information on ongoing studies of cell-cell signalling and transcriptional mechanisms that may regulate the development of His-Purkinje tissues.

• Differential regulation of the cardiac sodium calcium exchanger promoter in adult and neonatal cardiomyocytes by Nkx2.5 and serum response factor.

  Authors: Joachim G Müller, Jerry T Thompson, Angela M Edmonson, Mary S Rackley, Hideko Kasahara, Seigo Izumo, Tim C McQuinn, Donald R Menick, Terrence X O'Brien

  Journal of molecular and cellular cardiology. 08/2002; 34(7):807-21.

  Nkx2.5 and serum response factor (SRF) are critically important transcription factors in cardiac morphogenesis. They are also widely expressed in adult cardiomyocytes, but there is little data toNkx2.5 and serum response factor (SRF) are critically important transcription factors in cardiac morphogenesis. They are also widely expressed in adult cardiomyocytes, but there is little data to indicate their possible role in adult cardiac cells. In this paper we demonstrate that the interaction of Nkx2.5 and SRF in cardiac-specific gene regulation is different between neonatal and adult cardiomyocytes. Our experimental model utilizes transient transfection and adenovirus mediated gene transfer of the proximal promoter fragment of the cardiac isoform of the sodium-calcium exchanger gene (NCX1). This promoter construct (NCX184) contains a single Nkx2.5-response element (NKE) and a single serum response element (CArG). In rat neonatal cardiomyocytes NCX184 activity is substantially induced with Nkx2.5 or SRF and additively with both. Mutagenesis of these NKE and CArG elements demonstrated the specificity of the interactions, which was confirmed with gel retardation analysis of cardiac ventricular tissue. In contrast, in adult cardiomyocytes, co-infection of Nkx2.5 and SRF adenovirus vectors showed Nkx2.5 induction but SRF did not have additive effects on NCX1 promoter regulation. As opposed to NCX1, the proximal atrial natriuretic factor (ANF) promoter was regulated identically in response to SRF and Nkx2.5 in both adult and neonatal cardiomyocytes. These results show that Nkx2.5-SRF interactions are capable of producing different transcriptional responses in adult versus neonatal cardiomyocytes, implying important differences in NCX1 promoter tertiary complex formation dependent on developmental stage.

• Coronary arteriogenesis and differentiation of periarterial Purkinje fibers in the chick heart: is there a link?

  Authors: Brett S Harris, Terrence X O'Brien, Robert G Gourdie

  Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. 02/2002; 29(4):262-70.

  In the following review, we outline the cellular ontogeny and time course of coronary artery development within the vertebrate heart. Our eventual focus will be the potential role of arteriogenesisIn the following review, we outline the cellular ontogeny and time course of coronary artery development within the vertebrate heart. Our eventual focus will be the potential role of arteriogenesis in the differentiation of a subset of specialized conduction cells in the chick heart. We begin by briefly outlining early heart formation, showing how the outermost layer of the looped, tube heart--the epicardium--is of extracardiac origin and provides the progenitor cells to the entire vascular bed. Subsequently, we summarize the events of coronary arterial development that follow epicardialization. Finally, we discuss work in the chick that indicates how arteries form pioneering, directional conduits through ventricular tissue, adjacent to which myocardial cells differentiate to form the most peripheral component of the avian conduction system--a network of periarterial Purkinje fibers.