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Title: Arrhythmogenesis in pulmonary hypertension
Author: Temple, Ian Peter
ISNI:       0000 0004 5353 2246
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2014
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Background: Pulmonary arterial hypertension (PAH) is a condition with severe morbidity and mortality. It is associated with an increase in incidence of all forms of arrhythmias which further increase morbidity and mortality. The monocrotaline (MCT) model of pulmonary hypertension (PH) in the rat is analogous to PAH in humans and was used to study how PH causes arrhythmias. Methods: A single injection of MCT or a volume matched saline injection (control) was given to the rats on day 0 of the protocol. The hearts of both groups of rats were studied in vivo with echocardiography (echo) and electrocardiogram (ECG). The rat’s condition was monitored and they were electively sacrificed when they showed symptoms or on day 28. Live cardiac tissue was studied using the Langendorff preparation and a right atrial preparation that incorporated the sinoatrial (SA) and atrioventricular (AV) nodes. Molecular biology techniques including reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were used identify changes in the heart caused by PH. The effects of macitentan, an endothelin receptor antagonist used in the treatment of PAH, on the MCT injected rats was assessed using echo and ECGResults: Echo demonstrated that the MCT treated rats developed severe pulmonary hypertension with a decreased pulmonary artery acceleration time (P<0.005) and an increased pulmonary artery deceleration (P<0.005). The MCT treated rats also developed right ventricular hypertrophy (P<0.05) and dilation (P<0.005). The in vivo ECG demonstrated QT prolongation (P<0.005). Ex vivo functional experiments demonstrated QT prolongation (P<0.005) and prolonged ventricular effective refractory period (P<0.005). AV node dysfunction was also seen in the ex vivo experiments with an increased AV effective refractory period (P<0.05), AV functional refractory period (P<0.05) and incidence of complete heart block (P<0.05). RT-qPCR demonstrated significant changes in the mRNA expression of several ion channels and exchanges, Ca2+ handling proteins and autonomic receptors including a downregulation of HCN4 and CaV1.2 in the AV nodal tissues (P<0.05). Treatment of established pulmonary hypertension led to a reduction in the prolongation of the QT interval caused by MCT administration at day 21 (P<0.05).Conclusions: PH causes arrhythmogenic changes including prolonged repolarisation in the working myocardium and AV node dysfunction. These changes may be caused by dysregulation of ion channels and Ca2+ handling proteins. These ion channels and Ca2+handling proteins may play a key role in both physiological and pathological processes within the AV node.
Supervisor: Boyett, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: atrioventricular node ; ion channel