Heart Rate Variability and Pacemaker Cell Deterioration in Aging

Researchers here report on the details of pacemaker cell decline in aging. These cells drive the heartbeat, but as is the case for all tissues, they and their environment become damaged and dysfunctional in later life. Signaling mechanisms attempt to compensate, but that compensation is imperfect, and itself subject to the effects of damage:

Healthy heart beating intervals (BIs) are not strictly constant, but rather exhibit beat-to-beat variations, imparting complexity to the heart rhythm. Beating Interval Variability (BIV) reduction is a predictor of heart diseases and an increased mortality rate. Although the average basal BI remains constant with advancing age, the basal BIV is found to be reduced. In contrast to the preservation of the average basal BI, the average intrinsic BI, that is, in the absence of autonomic neural input, is found to be prolonged with advanced age. Whether and how the intrinsic BIV is altered in advanced age and the identities of mechanisms that underlie the changes in the BI-BIV relationship that accompany advancing age have not been well characterized.

Two main mechanisms regulate the average BI and BIV: (i) stimulation of extrinsic autonomic receptors on pacemaker cells (i.e. β-adrenergic receptors or cholinergic receptors) within the sinoatrial node (SAN) controlled by the balance between sympathetic and parasympathetic neural impulses to the heart and (ii) constitutive signaling intrinsic to pacemaker cell via Ca2+-calmodulin adenylyl cyclase (AC) types 1 and 8, which, in the absence of autonomic receptor stimulation, drives many of the same cell mechanisms that are modulated by autonomic receptor stimulation. Both neural input to pacemaker cells and mechanisms intrinsic to pacemaker cells deteriorate with advancing age.

We hypothesized that age-associated changes in average BI and BIV result from the alteration in both intrinsic and neural input signaling. We analyzed BI dynamics in mice of varying ages: (i) in vivo, when the autonomic input to the sinoatrial node is intact; (ii) during autonomic denervation in vivo; and (iii) ex vivo, in the intact isolated SAN tissue (i.e. in which the autonomic neural input is absent). BIV was quantified and although the average basal BI did not significantly change with age under intrinsic conditions in vivo and in the intact isolated pacemaker tissue, the average BI was prolonged in advanced age. In vivo basal BIV indices were found to be reduced with age, but this reduction diminished in the intrinsic state. However, in pacemaker tissue BIV indices increased in advanced age vs. adults. In the isolated pacemaker tissue, the sensitivity of the average BI and BIV in response to autonomic receptor stimulation or activation of mechanisms intrinsic to pacemaker cells by broad-spectrum phosphodiesterase inhibition declined in advanced age. Thus, changes in mechanisms intrinsic to pacemaker cells increase the average BIs and BIV in the mice of advanced age. Autonomic neural input to pacemaker tissue compensates for failure of molecular intrinsic mechanisms to preserve average BI. But this compensation reduces the BIV due to both the imbalance of autonomic neural input to the pacemaker cells and altered pacemaker cell responses to neural input.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12483/

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