Heart rate variability (beat-to-beat changes in the RR interval) has attracted considerable attention over the last 30+ years (PubMed currently lists >17,000 publications). Clinically, a decrease in heart rate variability is correlated to higher morbidity and mortality in diverse conditions, from heart disease to foetal distress. It is usually attributed to fluctuation in cardiac autonomic nerve activity. We calculated heart rate variability parameters from a variety of cardiac preparations (including humans, living animals, Langendorff-perfused heart and single sinoatrial nodal cell) in diverse species, combining this with data from previously published papers. We show that regardless of conditions, there is a universal exponential decay-like relationship between heart rate variability and heart rate. Using two biophysical models, we develop a theory for this, and confirm that heart rate variability is primarily dependent on heart rate and cannot be used in any simple way to assess autonomic nerve activity to the heart. We suggest that the correlation between a change in heart rate variability and altered morbidity and mortality is substantially attributable to the concurrent change in heart rate. This calls for re-evaluation of the findings from many papers that have not adjusted properly or at all for heart rate differences when comparing heart rate variability in multiple circumstances.

Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, If. Block of If abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro. We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training.

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The sinoatrial node is the primary pacemaker of the heart. Nodal dysfunction with aging, heart failure, atrial fibrillation, and even endurance athletic training can lead to a wide variety of pathological clinical syndromes. Recent work utilizing molecular markers to map the extent of the node, along with the delineation of a novel paranodal area intermediate in characteristics between the node and the surrounding atrial muscle, has shown that pacemaker tissue is more widely spread in the right atrium than previously appreciated. This can explain the phenomenon of a "wandering pacemaker" and concomitant changes in the P-wave morphology. Extensive knowledge now exists regarding the molecular architecture of the node (in particular, the expression of ion channels) and how this relates to pacemaking. This review is an up-to-date summary of the current state of our appreciation of the above topics.

The spontaneous rhythmic action potentials generated by the sinoatrial node (SAN), the primary pacemaker in the heart, dictate the regular and optimal cardiac contractions that pump blood around the body. Although the heart rate of humans is substantially slower than that of smaller experimental animals, current perspectives on the biophysical mechanisms underlying the automaticity of sinoatrial nodal pacemaker cells (SANCs) have been gleaned largely from studies of animal hearts. Using human SANCs, we demonstrated that spontaneous rhythmic local Ca2+ releases generated by a Ca2+ clock were coupled to electrogenic surface membrane molecules (the M clock) to trigger rhythmic action potentials, and that Ca2+–cAMP–protein kinase A (PKA) signaling regulated clock coupling. When these clocks became uncoupled, SANCs failed to generate spontaneous action potentials, showing a depolarized membrane potential and disorganized local Ca2+ releases that failed to activate the M clock. β-Adrenergic receptor (β-AR) stimulation, which increases cAMP concentrations and clock coupling in other species, restored spontaneous, rhythmic action potentials in some nonbeating “arrested” human SANCs by increasing intracellular Ca2+ concentrations and synchronizing diastolic local Ca2+ releases. When β-AR stimulation was withdrawn, the clocks again became uncoupled, and SANCs reverted to a nonbeating arrested state. Thus, automaticity of human pacemaker cells is driven by a coupled-clock system driven by Ca2+-cAMP-PKA signaling. Extreme clock uncoupling led to failure of spontaneous action potential generation, which was restored by recoupling of the clocks. Clock coupling and action potential firing in some of these arrested cells can be restored by β-AR stimulation–induced augmentation of Ca2+-cAMP-PKA signaling.