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Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/72983

Type: Journal article
Title: Cardiac arrhythmia mechanisms in rats with heart failure induced by pulmonary hypertension
Author: Benoist, David
Stones, Rachel
Drinkhill, Mark J.
Benson, Alan P.
Yang, Zhaokang
Cassan, Cecile
Gilbert, Stephen H.
Saint, David Albert
Cazorla, Olivier
Steele, Derek S.
Bernus, Olivier
White, Edward
Citation: American Journal of Physiology - Heart and Circulatory Physiology, 2012; 302(11):H2381-H2395
Publisher: American Physiological Society
Issue Date: 2012
ISSN: 0363-6135
School/Discipline: School of Medical Sciences : Physiology
Statement of
Responsibility: 
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, and Ed White
Abstract: Pulmonary hypertension provokes right heart failure and arrhythmias. Better understanding of the mechanisms underlying these arrhythmias is needed to facilitate new therapeutic approaches for the hypertensive, failing right ventricle (RV). The aim of our study was to identify the mechanisms generating arrhythmias in a model of RV failure induced by pulmonary hypertension. Rats were injected with monocrotaline to induce either RV hypertrophy or failure or with saline (control). ECGs were measured in conscious, unrestrained animals by telemetry. In isolated hearts, electrical activity was measured by optical mapping and myofiber orientation by diffusion tensor-MRI. Sarcoplasmic reticular Ca2+ handling was studied in single myocytes. Compared with control animals, the T-wave of the ECG was prolonged and in three of seven heart failure animals, prominent T-wave alternans occurred. Discordant action potential (AP) alternans occurred in isolated failing hearts and Ca2+ transient alternans in failing myocytes. In failing hearts, AP duration and dispersion were increased; conduction velocity and AP restitution were steeper. The latter was intrinsic to failing single myocytes. Failing hearts had greater fiber angle disarray; this correlated with AP duration. Failing myocytes had reduced sarco(endo)plasmic reticular Ca2+-ATPase activity, increased sarcoplasmic reticular Ca2+-release fraction, and increased Ca2+ spark leak. In hypertrophied hearts and myocytes, dysfunctional adaptation had begun, but alternans did not develop. We conclude that increased electrical and structural heterogeneity and dysfunctional sarcoplasmic reticular Ca2+ handling increased the probability of alternans, a proarrhythmic predictor of sudden cardiac death. These mechanisms are potential therapeutic targets for the correction of arrhythmias in hypertensive, failing RVs.
Keywords: electrocardiography; monocrotaline; calcium signaling; voltage-sensitive dye imaging; alternans
Rights: Copyright © 2012 the American Physiological Society
RMID: 0020119465
DOI: 10.1152/ajpheart.01084.2011
Appears in Collections:Physiology publications
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