Abstract
The function of the sinoatrial node (SAN), the pacemaker of the heart, declines with age, resulting in increased incidence of sinoatrial node dysfunction (SND) in older adults. The present study assesses potential ionic mechanisms underlying age associated SND. Two group studies have identified complex and various changes in some of membrane ion channels in aged rat SAN, the first group (Aging Study-1) indicates a considerable changes of gene expression with up-regulation of mRNA in ion channels of Cav1.2, Cav1.3 and KvLQT1, Kv4.2, and the Ca2+ handling proteins of SERCA2a, and down-regulation of Cav3.1, NCX, and HCN1 and the Ca2+-clock proteins of RYR2. The second group (Aging Study-2) suggests a different pattern of changes, including down regulation of Cav1.2, Cav1.3 and HCN4, and RYR2, and an increase of NCX and SERCA densities and proteins. Although both data sets shared a similar finding for some specific ion channels, such as down regulation of HCN4, NCX, and RYR2, there are contradictory changes for some other membrane ion channels, such as either up-regulation or down-regulation of Cav1.2, NCX and SERCA2a in aged rat SAN. The present study aims to test a hypothesis that age-related SND may arise from different ionic and molecular remodeling patterns. To test this hypothesis, a mathematical model of the electrical action potential of rat SAN myocytes was modified to simulate the functional impact of age-induced changes on membrane ion channels and intracellular Ca2+ handling as observed in Aging Study-1 and Aging Study-2. The role and relative importance of each individually remodeled ion channels and Ca2+-handling in the two datasets were evaluated. It was shown that the age-induced changes in ion channels and Ca2+-handling, based on either Aging Study-1 or Aging Study-2, produced similar bradycardic effects as manifested by a marked reduction in the heart rate (HR) that matched experimental observations. Further analysis showed that although the SND arose from an integrated action of all remodeling of ion channels and Ca2+-handling in both studies, it was the change to ICaL that played the most important influence.
Highlights
The sinoatrial node (SAN) is the primary pacemaker of the heart
Both aging datasets produced a similar consequence of agingrelated bradycardia, i.e., a slower pacemaking rate in the older adult compared with the adult condition, there are dramatic differences in the underlying remodeling of membrane ion channels and the Ca2+-handling
Figure 4Ai shows the simulated pacemaking APs based on data from Aging Study-1, with considerations only of an increase of ICa,L by 25%, Ca2+ uptake by 15%, and a decrease in INaCa by 6% for the older adult condition [data based on the mRNA expression data in Tellez et al (2011) study]
Summary
The sinoatrial node (SAN) is the primary pacemaker of the heart It is situated in the superior right atrium and produces a sequence of auto-rhythmic electrical activities that control the heartbeat (Baruscotti and Robinson, 2007). Dysfunction of the sinoatrial node (SND) associated with “sick sinus syndrome” (SSS) manifests as pathological bradycardia or systolic pauses (Haqqani and Kalman, 2007), producing inadequate blood supply to satisfy the demands of the body. This condition leads to symptoms such as dizziness and syncope (Haqqani and Kalman, 2007), though the initial stages of SND may be latent and asymptomatic (Choudhury et al, 2015). Increased fibrosis and degenerative changes in physiological properties of the SAN may cause SND (Baruscotti and Robinson, 2007; Zhang et al, 2007; Choudhury et al, 2015)
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