Résumé
Background: Ageing is an important risk factor for cardiovascular disease. Regardless of lifestyle, aged people suffer from a decrease in maximal Heart Rate (HR) and HR Variability (HRV). Abnormal activity of the Sino-Atrial Node (SAN) and altered autonomic modulation, have been related to HR decline in aged people. However, their relative contribution to the pathophysiology process of cardiovascular ageing remains poorly understood. Purpose: The aim of this study was to investigate cardiac pacemaker activity and the modulation mediated by the autonomic nervous system on the heart of mice in vivo and ex vivo, to understand the mechanism that deregulates HR and HRV in ageing. Methods: We analyzed HR and HRV in young (3 months) and aged (24 months) mice by electrocardiogram (ECG) recording obtained from telemetric ECG and ECG tunnel. To assess the function of the autonomic nervous system, we measured the concentration of catecholamine in the urines. As well, we recorded the SAN activity ex vivo, under control and after β-adrenergic activation, and stimulation of L-type Ca2+ channels, to identify dysfunctions of the intrinsic mechanism of pacemaker activity. Results: Compared to young mice, ECG telemetry showed higher HR, a low Coefficient of Variability of RR intervals (CVRR) and a significant increase of noradrenaline levels. When analyzing the results obtained from the ECG tunnel technique that likely maintain in a stressful situation the animals, we observed a slower HR in aged mice. We noticed that the HR of young mice recorded in constricted animals by ECG tunnel was significantly higher than freely moving animals recorded by ECG telemetry, confirming the effect of stress under constriction. Conversely, aged mice showed the same HR under both situations, suggesting a failure to respond to constriction stress. Concerning the ex vivo results, we observed that the SAN of aged mice generated a slower pacemaker activity than young ones and presented a blunted chronotropic response to βadrenergic activation and pharmacologic stimulation of L-type Ca2+ channels. Conclusions: The HR phenotype of aged mice could result from a combination of stress-induced sympathetic overdrive under lower external temperature, associated with altered intrinsic pacemaker activity and βadrenergic chronotropic response. Indeed, high HR in freely moving aged mice, coupled to the increase of noradrenaline could be explained by a chronic stress related to low external temperature in animal facility (21-22 C°). In addition, the failure to respond to constriction stress in aged mice suggested the impairment of the β-adrenergic modulation which was confirmed by the blunted response of the SAN ex vivo.