Acute myocardial ischaemia and reperfusion (I-R) are major causes of ventricular arrhythmias. In the chronic post-ischaemic heart, the presence of a healed fibrotic scar contributes to the occurrence of malignant arrhythmias, and development of post-myocardial infarction (MI) left ventricular (LV) remodelling and heart failure (HF). The aim of the work in this thesis was to investigate if ursodeoxycholic acid (UDCA) protects against acute I-R-induced arrhythmias, and if it plays cardioprotective and anti-arrhythmic roles in the chronic post-MI adult myocardium.
An ex vivo rat model of acute I-R was used to study the effect of UDCA on arrhythmia incidence. UDCA administration reduced acute ischaemia-induced arrhythmias, with no effect on reperfusion arrhythmias. The antiarrhythmic effect of UDCA is partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity (CV) slowing, and the preservation of Connexin43 phosphorylation during acute ischaemia.
Multiple in vitro models of cardiac fibrosis were used to study the potential of UDCA as treatment of cardiac fibrosis. UDCA was proven to reduce cardiac fibrosis and preserve the associated changes in contractile functions and electrophysiology. The antifibrotic mechanism of action of UDCA is partially mediated by TGR5 modulation via dephosphorylation of ERK protein.
A sixteen-week post-MI model was generated to explore the effects of UDCA on late post-MI arrhythmias and LV remodeling. UDCA prevented the adverse LV remodeling associated with the progression of MI and reduced fibrosis and the healed ischaemic border zone (IBZ) sizes. This resulted in reduced late susceptibility to ventricular arrhythmias and improved CV across the IBZ in UDCA-treated hearts at 16 weeks post MI. We generated robust novel data highlighting the potential application of UDCA in the prevention of ventricular arrhythmias during acute MI in the adult myocardium as well as against cardiac arrhythmias that are associated with cardiac fibrosis, due to its cardioprotective effect in the post-MI heart.