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Adult Left Atrium: Reduction of Pitx2c Expression Promotes Atrial Fibrillation Inducibility and Complex Changes in Gene Expression

Posted in Congenital Heart Disease, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged , , , on December 18, 2013| Leave a Comment »

Adult Left Atrium: Reduction of Pitx2c Expression Promotes Atrial Fibrillation Inducibility and Complex Changes in Gene Expression

Aviva Lev-Ari, PhD, RN

PITX2c Is Expressed in the Adult Left Atrium, and Reducing Pitx2c Expression Promotes Atrial Fibrillation Inducibility and Complex Changes in Gene Expression

Paulus Kirchhof, MD*, Peter C. Kahr*, Sven Kaese, Ilaria Piccini, PhD, Ismail Vokshi, BSc, Hans-Heinrich Scheld, MD, Heinrich Rotering, MD, Lisa Fortmueller, MD (vet),Sandra Laakmann, MD (vet), Sander Verheule, PhD, Ulrich Schotten, MD, PhD,Larissa Fabritz, MD and Nigel A. Brown, PhD

Author Affiliations

From the Department of Cardiology and Angiology (P.K., P.C.K., S.K., I.P., L.F., S.L., L.F.) and the Department of Thoracic and Cardiovascular Surgery (H.-H.S., H.R.), University Hospital Muenster, Germany; Division of Biomedical Sciences (P.C.K., I.V., N.A.B.), St. George’s, University of London, United Kingdom; and the Department of Physiology (S.V., U.S.), Maastricht University, The Netherlands.

Correspondence to Nigel A. Brown, PhD, Division of Biomedical Sciences, St George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK. E-mail  nbrown@sgul.ac.uk

↵* Drs Kirchhof and Kahr contributed equally to this work.

Abstract

Background— Intergenic variations on chromosome 4q25, close to the PITX2 transcription factor gene, are associated with atrial fibrillation (AF). We therefore tested whether adult hearts express PITX2 and whether variation in expression affects cardiac function.

Methods and Results— mRNA for PITX2 isoform c was expressed in left atria of human and mouse, with levels in right atrium and left and right ventricles being 100-fold lower. In mice heterozygous for Pitx2c (Pitx2c+/−), left atrial Pitx2c expression was 60% of wild-type and cardiac morphology and function were not altered, except for slightly elevated pulmonary flow velocity. Isolated Pitx2c+/−hearts were susceptible to AF during programmed stimulation. At short paced cycle lengths, atrial action potential durations were shorter in Pitx2c+/− than in wild-type. Perfusion with the β-receptor agonist orciprenaline abolished inducibility of AF and reduced the effect on action potential duration. Spontaneous heart rates, atrial conduction velocities, and activation patterns were not affected in Pitx2c+/− hearts, suggesting that action potential duration shortening caused wave length reduction and inducibility of AF. Expression array analyses comparing Pitx2c+/− with wild-type, for left atrial and right atrial tissue separately, identified genes related to calcium ion binding, gap and tight junctions, ion channels, and melanogenesis as being affected by the reduced expression of Pitx2c.

Conclusions— These findings demonstrate a physiological role for PITX2 in the adult heart and support the hypothesis that dysregulation of PITX2 expression can be responsible for susceptibility to AF.

SOURCE:

Circulation: Cardiovascular Genetics.2011; 4: 123-133

Published online before print January 31, 2011,

doi: 10.1161/ CIRCGENETICS.110.958058

 

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