The age-related reduction in adrenergic response as a limitation of cardiac function in old age

A reduction in the efficacy of the beta-adrenergic receptor (βAR) signalling response is thought to be a key component of the reduction in cardiac reserve in old age. However, evidence is far from unanimous regarding dynamic changes in β1AR and immediate signalling with ageing. Therefore, changes in downstream effector mechanisms may be responsible for a significant component of the reduced adrenergic response seen in advanced age. At the myocyte level, β1AR signalling heavily controls action potential (AP) repolarisation during stress and this, in part, facilitates the ability to follow higher cardiac rates. A large body of evidence has demonstrated that AP repolarisation is prolonged in old age and whilst its response to adrenergic stimulation has been postulated to be reduced in old age, little physiologically relevant evidence exists. This project aimed to: assess the influence of age on ventricular myocyte AP form and response to adrenergic stimulation, explore potential key components responsible for the duration of the AP and thus set minimal stable cycle length of the heart during exercise and finally to modify a recent computational electrophysiological adult rat heart model (Leeds Rat (LR) model) to recreate the AP and AP response to adrenergic stimulation observed in this work and others. Whole-cell patch-clamp investigations on adult (3 months of age) and old (22 – 23 months of age) ventricular myocytes from male Wistar rat hearts found time to achieve 90 % full repolarisation (APD90) prolonged (29 %) in old rats compared with adult rats. Peak L-type Ca2+ channel (LTCC) current remained similar with ageing, however the influence of chromanol 293b-sensitive current on late AP repolarisation reduced in old rats compared with adult rats during adrenergic stimulation. Other measures of chromanol 293b-sensitive current (51 - 99 %) alongside the response to adrenergic stimulation also reduced in old rats compared with adult rats. Similarly with ageing, inward rectifying K+ channel (IK1) current reduced (> 95 %). Conversely, rapid delayed rectifying K+ channel (IKr) current was greater in old rats compared with adult rats (235 – 467 %) during adrenergic stimulation. Finally, the modified LR (mLR) model was able to reproduce ventricular myocyte APD from adult rats comparable to experimental data at a range of pacing frequencies during basal and adrenergic stimulation conditions. This work provides novel reference values for future electrophysiological and computational studies alongside the foundation for the development of a computational old rat heart model which will aid understanding of the loss of cardiac reserve in old age. This work also highlights the need for further AP and ion channel investigations at elevated pacing frequencies that more closely emulate a physiological exercise response.