Abstract
Type 2 diabetes is one of the largest and fastest growing health issues globally and in New Zealand, putting an enormous burden on the health care system. It is known that there is a close link between diabetes and cardiovascular disease (CVD), and that diabetic patients with CVD have a higher mortality compared to patients presenting with CVD or diabetes alone. Diabetes promotes sinoatrial node dysfunction and is known to cause heart rate (HR) dysfunction; therefore, the aims of this thesis was to investigate the why HR changes in diabetic hearts using optical mapping. In particular, my thesis focused on the altered expression of hyperpolarisation-activated cyclic nucleotide gated channel 4 (HCN4) and the altered function of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), two important proteins in the so-called voltage and Ca2+ clocks which underpin the generation of the heartbeat. I developed a novel custom chamber suitable for the optical mapping of isolated sinoatrial node tissue. I also determined the contribution of SERCA2a to HR, in which I hypothesised a decrease in HR upon SERCA2a inhibition with thapsigargin, with a lower concentration required for maximal slowing of HR in the type 2 diabetes (DM) sinoatrial node (SAN) compared to non-DM SAN. Contrary to my hypothesis, a significant increase in HR was observed upon SERCA2a inhibition with thapsigargin. In the presence of 1 μM thapsigargin HR was 121 ± 9.27 bpm compared 96 ± 9.8 bpm in the absence of thapsigargin (p<0.05). The thapsigargin results in this thesis highlight the important relationship between SERCA2a activity and HR. As other studies have indicated diabetic patients have lower SERCA2a activity these data may indicate that the loss of SERCA2a activity in diabetes underpins the increased HR in patients with diabetes and CVD, as well as future directions for therapeutic approaches in patients with CVD.