ELECTROPHYSIOLOGICAL CHARACTERIZATION OF THE CARDIAC PACEMAKER ACTIVITY DURING AGING AND IN THE PRESENCE OF THE TRADITIONAL CHINESE MEDICINE DRUG TMYX

Age-dependent changes in murine cardiac pacemaker activity. Cardiovascular diseases (CDVs) are the main causes of death. The incidence of morbidity and mortality associated with CDVs increases exponentially in the elderly population due to the increase of both the number of old people and of the average lifespan (for example it is estimated that in the United States there will be 70 million people over the age of 65 by the year 2030, representing almost 25% of the population, 6 . Amongst the age-dependent cardiovascular diseases, the sinoatrial node dysfunction has a primary role 7 ; for this reason, there is a high interest in the study of the pathophysiological mechanisms that are at the basis of cardiac aging. It is known that in humans during ageing there is a decline in maximum heart rate (MHR) and a reduction in the intrinsic heart rate (IHR) 8,9 ; however basal heart rate (BHR) remains the same between the adults and the elderly 10 . We thus decided to better understand the age-associated mechanisms responsible for the changes in intrinsic and maximum heart rate but not in the basal heart rate, and we chose the mouse as a study model. We therefore first confirmed that in our murine model the IHR, but not the basal HR, decreases with ageing; and we also noticed that in adult mice the IHR and the BHR were similar. We focused our studies on the funny current since it is a main contributor to pacemaking generation and modulation and we observed a reduction of the current density and a negative shift of the activation curve in the old animals. We then evaluated the influence of the autonomic system and we found that in adult mice both branches of the autonomic system contribute similarly to HR, though in opposite directions; old mice instead had a lower vagal tone, leading to a reduction in the overall HRV as assessed by spectral analysis, and an increased sympathetic tone, leading to a larger vulnerability to spontaneous arrhythmias compared to adult. Our data highlight that this model recapitulates well the HR features observed in aged humans and can help understanding the mechanisms of the ageing-associated changes in heart chronotropism. The shift of the sympatho-vagal balance toward a sympathetic prevalence in the old animals may explain why, despite the difference in the intrinsic heart rate, the basal heart rate is similar between the two groups. While the current view is that the sympathetic increase is necessary to ensure the homeostatic balance of heart rate during ageing, it is also possible that the age-dependent increase of the sympathetic tone is the cause of the reduction of the intrinsic heart rate which therefore ultimately represents the compensatory effect.