Beta-adrenergic stimulation and cardiac arrhythmogenesis in the infarct border zone

• Main Author: Tomek, Jakub
• Other Authors: Bub, Gil ; Rodriguez, Blanca ; Paterson, David J.
• Published: University of Oxford 2017
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748718

Sudden cardiac death due to ventricular arrhythmias after myocardial infarction (MI) is a major cause of mortality worldwide. Following a MI, the heart undergoes considerable remodelling; however, the precise mechanisms of how the changes induce arrhythmia have not been fully elucidated. The role of sympathetic innervation in the infarct border zone (BZ) is particularly controversial: while historical evidence posits a strongly proarrhythmic role, recent clinical studies report that it is the lack of such innervation which is associated with future arrhythmic events. In this thesis, we aim to improve the understanding of the sympathetic nervous system after MI, focussing predominantly at how neurally mediated β-adrenergic stimulation affects cardiac alternans, an arrhythmic precursor which often affects post-MI hearts and is frequently observed before fibrillation. Using ex vivo rat hearts with a healed myocardial infarction, we demonstrate that infarcted hearts are vulnerable to alternans in the BZ. Pharmacological β-adrenergic stimulation, which emulates sympathetic nervous activation, powerfully attenuates alternans, supporting the view that the border zone innervation may play an important role in prevention of fibrillation. Furthermore, we develop a computer model of a ventricular myocyte which allows representation of the BZ phenotype, as well as β-adrenergic stimulation. The model behaves consistently with the experimental data obtained and its analysis reveals a mechanistic explanation for alternans attenuation via β-adrenergic stimulation. Finally, we provide a set of software tools for high-throughput processing of cardiac imaging data that we hope to be useful to be to the community. Our work helps resolve the controversy of the role of sympathetic innervation after myocardial infarction. It suggests a dual role for the cardiac sympathetic nervous system after MI: anti-arrhythmic via alternans attenuation, but pro-arrhythmic by increasing the heart rate. The results of this thesis have implications both for understanding of cardiac physiology, as well as for existing and future therapies.