There is a day-night rhythm in resting heart rate: faster during the awake period, and slower during the rest period. Importantly, these daily rhythms influence the timing of adverse cardiovascular events such as missed beats or even heart attacks.1 Now, researchers Alicia D’Souza and Mark Boyett at the University of Manchester have uncovered an unusual role for the sympathetic nervous system (SNS) in regulating this day-night cycle of resting heart rate.2
The team found that the SNS, which is typically associated with the “fight or flight” response, played an important role in regulating the resting heart rate on a day-night timescale. Unexpectedly, the intrinsic circadian rhythm of sympathetic nerve impulses regulated the transcription of ion channels in the heart’s pacemaker, the sinus node. This study builds on the team’s previous work studying the day-night rhythm of ion channels in other parts of the heart.3
“Understanding the remodeling that’s going on in the heart at the transcriptional level is pretty fascinating,” said Elizabeth Schroder Stumpf, a physiologist at the University of Kentucky, who was not involved in the study. “We now have data on the ventricle, atrium, and now the [sinus] node. That’s pretty cool.”
For nearly 100 years, the circadian rhythm of resting heart rate has been attributed to the parasympathetic nervous system, especially the vagus nerve in humans,4 which associates with “rest and digest.” However, the team previously found little evidence directly linking vagus nerve activity to slowing of the heart rate at night.3 In this new study, they showed that the heart’s pacemaker required SNS instead of parasympathetic nervous system input to regulate its day-night cycle.
In typical heart rate regulation by the SNS, catecholamines such as adrenaline are released from autonomic nerves in the sinus node, regulating heart rate on a timescale of seconds via short-term changes to ion channel conductance. However, this short-term regulation did not explain why the heart conduction system generally slowed down at night.
“All the arrows pointed to the fact that there might be an intrinsic rhythm with the ion channels and related proteins that set the function of the cardiac conduction system,” explained Alicia D’Souza, a cardiac physiologist at Imperial College London and coauthor of the study. “Was there an internal cycling of the expression levels of these key proteins and ion channels that underpinned pacemaking in the heart? So that’s where we started looking.”
Mice exhibit a well-documented circadian rhythm and ECG parameters comparable to humans, so the researchers pharmacologically blocked the SNS using the β-adrenergic receptor blocker, propranolol in mouse models. In the heart, β-adrenergic receptors are primarily responsible for responding to SNS signals.
With a sustained block of the SNS, the researchers observed loss of the day-night rhythm in sinus node pacemaking and in pacemaking ion channels. Surprisingly, the heart’s local circadian clock carried on ticking. Most of the transcripts that retained rhythmicity following the blockade were circadian clock or established clock-controlled transcription factors.
So, what caused this day-night rhythm in the heart? “Well, one thing is this local circadian clock, but what this paper shows is that there's something else, and that's the sympathetic nervous system,” said Mark Boyett, a physiologist at Manchester University and author of the study. “Unexpectedly, this is why we say it's a noncanonical role; it is acting on gene expression.”
Importantly, transcription factors in the sinus node lost rhythmicity following the sustained β-adrenergic blockade. Thus, the team proposed that day-night rhythms in the sinus node are orchestrated by rhythmic β-adrenergic input from the SNS to regulate ion channel gene expression. “It's a way of thinking about the involvement of the autonomic nervous system, not as commonly accepted, which is these very short range, immediate acute modulations of ion channel function, but through long range modulation by affecting gene expression in the heart or in the sinus node,” said D’Souza.
This study demonstrated for the first time that long-term pharmacological β-adrenergic blockade altered the day-night rhythm in heart rate. “In our previous work, we showed the ion channels involved, then we showed a role for the local clock,” D’Souza summarized, “Now we show that the local clock is not acting on its own but requires sympathetic input.”
By revealing a new role for the SNS in regulating resting heart rate, this study has implications for treating and preventing adverse cardiovascular events. “Frequently in cardiovascular disease arrhythmias, people are prescribed beta blockers,” said Stumpf, “Therefore, understanding the underlying regulatory mechanisms seems to be very important. It has the potential for the development of new chronotherapies that might mitigate disease risk in people.”
- McLoughlin SC, Haines P, FitzGerald GA. Clocks and cardiovascular function. Methods Enzymol. 2015;552:211-228.
- Anderson C, Forte G, Hu W, Zhang H, Boyett MR, D'Souza A. Non-canonical role of the sympathetic nervous system in the day-night rhythm in heart rate. Philos Trans R Soc Lond B Biol Sci. 2023;378(1879):20220179.
- D'Souza A, Wang Y, Anderson C, et al. A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate. Heart Rhythm. 2021;18(5):801-810.
- Boas EP, Weiss MM. The heart rate during sleep as determined by the cardiotachometer: its clinical significance. Journal of the American Medical Association. 1929;92(26):2162-2168.
