Ian P Temple1, Sunil Jit R J Logantha1, Mais Absi1, Yu Zhang1, Eleftheria Pervolaraki1, Joseph Yanni1, Andrew Atkinson1, Maria Petkova1, Gillian M Quigley1, Simon Castro1, Mark Drinkhill1, Heiko Schneider1, Oliver Monfredi1, Elizabeth Cartwright1, Min Zi1, Tomoko T Yamanushi1, Vaikom S Mahadevan1, Alison M Gurney1, Ed White1, Henggui Zhang1, George Hart1, Mark R Boyett2, Halina Dobrzynski1. 1. From the Institute of Cardiovascular Sciences (I.P.T., S.J.R.J.L., M.A., Y.Z., J.Y., A.A., M.P., G.M.Q., H.S., O.M., E.C., M.Z., A.M.G., G.H., M.R.B., H.D.) and School of Physics and Astronomy (S.C., H.Z.), University of Manchester, United Kingdom; School of Biomedical Sciences, University of Leeds, United Kingdom (E.P., M.D., E.W.); Kagawa Prefectural College of Health Sciences, Takamatsu, Japan (T.T.Y.); and Department of Medicine, University of California, San Francisco (V.S.M.). 2. From the Institute of Cardiovascular Sciences (I.P.T., S.J.R.J.L., M.A., Y.Z., J.Y., A.A., M.P., G.M.Q., H.S., O.M., E.C., M.Z., A.M.G., G.H., M.R.B., H.D.) and School of Physics and Astronomy (S.C., H.Z.), University of Manchester, United Kingdom; School of Biomedical Sciences, University of Leeds, United Kingdom (E.P., M.D., E.W.); Kagawa Prefectural College of Health Sciences, Takamatsu, Japan (T.T.Y.); and Department of Medicine, University of California, San Francisco (V.S.M.). mark.boyett@manchester.ac.uk.
Abstract
BACKGROUND: Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. METHODS AND RESULTS: The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right-sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV node); and quantitative PCR revealed a widespread downregulation of ion channel and related genes in the AV node (eg, >50% downregulation of Cav1.2/3 and HCN1/2/4 channels). Computer modeling predicted that the changes in the transcriptome if translated into protein and function would result in heart block. CONCLUSIONS: Pulmonary hypertension results in a derangement of the ion channel transcriptome in the AV node, and this is the likely cause of AV node dysfunction in this disease.
BACKGROUND: Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. METHODS AND RESULTS: The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right-sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV node); and quantitative PCR revealed a widespread downregulation of ion channel and related genes in the AV node (eg, >50% downregulation of Cav1.2/3 and HCN1/2/4 channels). Computer modeling predicted that the changes in the transcriptome if translated into protein and function would result in heart block. CONCLUSIONS: Pulmonary hypertension results in a derangement of the ion channel transcriptome in the AV node, and this is the likely cause of AV node dysfunction in this disease.
Authors: David Benoist; Rachel Stones; Mark J Drinkhill; Alan P Benson; Zhaokang Yang; Cecile Cassan; Stephen H Gilbert; David A Saint; Olivier Cazorla; Derek S Steele; Olivier Bernus; Ed White Journal: Am J Physiol Heart Circ Physiol Date: 2012-03-16 Impact factor: 4.733
Authors: David Benoist; Rachel Stones; Mark Drinkhill; Olivier Bernus; Ed White Journal: Am J Physiol Heart Circ Physiol Date: 2011-03-11 Impact factor: 4.733
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Authors: Benjamin Strauss; Yassine Sassi; Carlos Bueno-Beti; Zeki Ilkan; Nour Raad; Marine Cacheux; Malik Bisserier; Irene C Turnbull; Erik Kohlbrenner; Roger J Hajjar; Lahouaria Hadri; Fadi G Akar Journal: J Mol Cell Cardiol Date: 2018-11-28 Impact factor: 5.000