Publications by authors named "Wim Aanhaanen"

7 Publications

  • Page 1 of 1

Epicardial and Subsequent Endocardial Ablation in a Patient With Brugada Syndrome.

JACC Clin Electrophysiol 2018 09;4(9):1268-1270

Department of Cardiology, Isala Heart Center, Zwolle, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jacep.2018.05.013DOI Listing
September 2018

Origin and development of the atrioventricular myocardial lineage: insight into the development of accessory pathways.

Birth Defects Res A Clin Mol Teratol 2011 Jun 31;91(6):565-77. Epub 2011 May 31.

Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, Amsterdam, The Netherlands.

Defects originating from the atrioventricular canal region are part of a wide spectrum of congenital cardiovascular malformations that frequently affect newborns. These defects include partial or complete atrioventricular septal defects, atrioventricular valve defects, and arrhythmias, such as atrioventricular re-entry tachycardia, atrioventricular nodal block, and ventricular preexcitation. Insight into the cellular origin of the atrioventricular canal myocardium and the molecular mechanisms that control its development will aid in the understanding of the etiology of the atrioventricular defects. This review discusses current knowledge concerning the origin and fate of the atrioventricular canal myocardium, the molecular mechanisms that determine its specification and differentiation, and its role in the development of certain malformations such as those that underlie ventricular preexcitation.
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http://dx.doi.org/10.1002/bdra.20826DOI Listing
June 2011

Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice.

J Clin Invest 2011 Feb 25;121(2):534-44. Epub 2011 Jan 25.

Heart Failure Research Center, University of Amsterdam, Amsterdam, The Netherlands.

Ventricular preexcitation, a feature of Wolff-Parkinson-White syndrome, is caused by accessory myocardial pathways that bypass the annulus fibrosus. This condition increases the risk of atrioventricular tachycardia and, in the presence of atrial fibrillation, sudden death. The developmental mechanisms underlying accessory pathway formation are poorly understood but are thought to primarily involve malformation of the annulus fibrosus. Before birth, slowly conducting atrioventricular myocardium causes a functional atrioventricular activation delay in the absence of the annulus fibrosus. This myocardium remains present after birth, suggesting that the disturbed development of the atrioventricular canal myocardium may mediate the formation of rapidly conducting accessory pathways. Here we show that myocardium-specific inactivation of T-box 2 (Tbx2), a transcription factor essential for atrioventricular canal patterning, leads to the formation of fast-conducting accessory pathways, malformation of the annulus fibrosus, and ventricular preexcitation in mice. The accessory pathways ectopically express proteins required for fast conduction (connexin-40 [Cx40], Cx43, and sodium channel, voltage-gated, type V, α [Scn5a]). Additional inactivation of Cx30.2, a subunit for gap junctions with low conductance expressed in the atrioventricular canal and unaffected by the loss of Tbx2, did not affect the functionality of the accessory pathways. Our results suggest that malformation of the annulus fibrosus and preexcitation arise from the disturbed development of the atrioventricular myocardium.
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http://dx.doi.org/10.1172/JCI44350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026729PMC
February 2011

Developmental origin, growth, and three-dimensional architecture of the atrioventricular conduction axis of the mouse heart.

Circ Res 2010 Sep 29;107(6):728-36. Epub 2010 Jul 29.

Heart Failure Research Center, Academic Medical Center, University of Amsterdam, the Netherlands.

Rationale: The clinically important atrioventricular conduction axis is structurally complex and heterogeneous, and its molecular composition and developmental origin are uncertain.

Objective: To assess the molecular composition and 3D architecture of the atrioventricular conduction axis in the postnatal mouse heart and to define the developmental origin of its component parts.

Methods And Results: We generated an interactive 3D model of the atrioventricular junctions in the mouse heart using the patterns of expression of Tbx3, Hcn4, Cx40, Cx43, Cx45, and Nav1.5, which are important for conduction system function. We found extensive figure-of-eight rings of nodal and transitional cells around the mitral and tricuspid junctions and in the base of the atrial septum. The rings included the compact node and nodal extensions. We then used genetic lineage labeling tools (Tbx2(+/Cre), Mef2c-AHF-Cre, Tbx18(+/Cre)), along with morphometric analyses, to assess the developmental origin of the specific components of the axis. The majority of the atrial components, including the atrioventricular rings and compact node, are derived from the embryonic atrioventricular canal. The atrioventricular bundle, including the lower cells of the atrioventricular node, in contrast, is derived from the ventricular myocardium. No contributions to the conduction system myocardium were identified from the sinus venosus, the epicardium, or the dorsal mesenchymal protrusion.

Conclusions: The atrioventricular conduction axis comprises multiple domains with distinctive molecular signatures. The atrial part proliferates from the embryonic atrioventricular canal, along with myocytes derived from the developing atrial septum. The atrioventricular bundle and lower nodal cells are derived from ventricular myocardium.
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http://dx.doi.org/10.1161/CIRCRESAHA.110.222992DOI Listing
September 2010

Generation of mice with a conditional null allele for Tbx2.

Genesis 2010 Mar;48(3):195-9

Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.

The T-box transcription factor Tbx2 plays important roles in patterning and development, and has been implicated in cell-cycle regulation and cancer. Conventional disruption of Tbx2 results in abnormalities of the heart, limbs, eye and other structures, and early fetal lethality. To gain insight into the role of Tbx2 in different tissues and at different stages of development, we have generated a conditional null allele of Tbx2 by flanking Exon 2 with loxP sites (Tbx2(fl2)). Homozygous Tbx2(fl2) mice are viable and fertile, indicating that the Tbx2(fl2) allele is a fully functional Tbx2 allele. Cre-mediated recombination, using a ubiquitously active CMV-Cre line, results in deletion of Exon 2 and loss of protein expression. Embryos homozygous for the recombined allele (Tbx2(Delta2)) show the same heart and limb defects as conventional Tbx2-deficient embryos. This Tbx2 conditional null allele will be a valuable tool to uncover tissue-specific roles of Tbx2 in development and disease.
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http://dx.doi.org/10.1002/dvg.20596DOI Listing
March 2010

The Tbx2+ primary myocardium of the atrioventricular canal forms the atrioventricular node and the base of the left ventricle.

Circ Res 2009 Jun 7;104(11):1267-74. Epub 2009 May 7.

Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

The primary myocardium of the embryonic heart, including the atrioventricular canal and outflow tract, is essential for septation and valve formation. In the chamber-forming heart, the expression of the T-box transcription factor Tbx2 is restricted to the primary myocardium. To gain insight into the cellular contributions of the Tbx2+ primary myocardium to the components of the definitive heart, genetic lineage tracing was performed using a novel Tbx2Cre allele. These analyses revealed that progeny of Tbx2+ cells provide an unexpectedly large contribution to the Tbx2-negative ventricles. Contrary to common assumption, we found that the embryonic left ventricle only forms the left part of the definitive ventricular septum and the apex. The atrioventricular node, but not the atrioventricular bundle, was found to derive from Tbx2+ cells. The Tbx2+ outflow tract formed the right ventricle and right part of the ventricular septum. In Tbx2-deficient embryos, the left-sided atrioventricular canal was found to prematurely differentiate to chamber myocardium and to proliferate at increased rates similar to those of chamber myocardium. As a result, the atrioventricular junction and base of the left ventricle were malformed. Together, these observations indicate that Tbx2 temporally suppresses differentiation and proliferation of primary myocardial cells. A subset of these Tbx2Cre-marked cells switch off expression of Tbx2, which allows them to differentiate into chamber myocardium, to initiate proliferation, and to provide a large contribution to the ventricles. These findings imply that errors in the development of the early atrioventricular canal may affect a much larger region than previously anticipated, including the ventricular base.
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http://dx.doi.org/10.1161/CIRCRESAHA.108.192450DOI Listing
June 2009

Synthesis and evaluation of iodinated TZTP-derivatives as potential radioligands for imaging of muscarinic M2 receptors with SPET.

Nucl Med Biol 2004 Jan;31(1):111-23

Graduate School of Neurosciences, Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

A series of iodinated thiadiazolyltetrahydro-1-methyl-pyridine (TZTP) compounds was synthesized and evaluated in vitro and in vivo as potential radioligands for imaging of the muscarinic M2 receptor subtype with SPET. One of these compounds, 5-(E)-iodopentenylthio-TZTP, has high in vitro affinity (Ki = 4.9 nM) and moderate selectivity for the muscarinic M2 receptor subtype. Although the uptake pattern in the biodistribution studies in rats is consistent with muscarinic M2 receptor disribution, specific in vivo binding to these receptors could not be demonstrated. The usefulness of this tracer in human SPET imaging may therefore be limited.
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http://dx.doi.org/10.1016/s0969-8051(03)00095-7DOI Listing
January 2004
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