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. Author manuscript; available in PMC: 2023 Mar 2.
Published in final edited form as: J Physiol. 2022 Apr 7;600(9):2037–2048. doi: 10.1113/JP282402

The Role of the Cardiomyocyte Circadian Clocks in Ion Channel Regulation and Cardiac Electrophysiology

Elizabeth A Schroder 1,2, Makoto Ono 1, Sidney R Johnson 1, Ezekiel R Rozmus 1, Don E Burgess 1, Karyn A Esser 3, Brian P Delisle 1
PMCID: PMC9980729  NIHMSID: NIHMS1875091  PMID: 35301719

Abstract

Daily variations in cardiac electrophysiology and the incidence for different types of arrhythmias reflect ≈24-hour changes in the environment, behavior, and internal circadian rhythms. This article focuses on studies that use animal models to separate the impact that circadian rhythms, as well as changes in the environment and behavior, have on 24-hour rhythms in heart rate and ventricular repolarization. Circadian rhythms are initiated at the cellular level by circadian clocks, transcription-translation feedback loops that cycle with a periodicity of 24-hours. Several studies now show the circadian clock in cardiomyocytes regulates the expression of cardiac ion channels by multiple mechanisms; underlies time-of-day changes in sinoatrial node excitability/intrinsic heart rate; and limits the duration of the ventricular action potential waveform. However, the 24-hour rhythms in heart rate and ventricular repolarization are primarily driven by autonomic signaling. A functional role for the cardiomyocyte circadian clock appears to buffer the heart against perturbations. For example, the cardiomyocyte circadian clock limits QT-interval prolongation (especially at slower heart rates), and it may facilitate the realignment of the 24-hour rhythm in heart rate to abrupt changes in the light cycle. Additional studies show modifying rhythmic behaviors (including feeding behavior) can dramatically impact the 24-hour rhythms in heart rate and ventricular repolarization. If these mechanisms are conserved, these studies suggest targeting endogenous circadian mechanisms in the heart, as well as modifying the timing of certain rhythmic behaviors, could emerge as therapeutic strategies to support heart function against perturbations and regulate 24-hour rhythms in cardiac electrophysiology.

Graphical Abstract

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Introduction

The field of clinical cardiology commonly uses the term “circadian” to describe time-of-day changes in physiological and pathophysiological processes based on local clock time or in reference to waking. Several studies demonstrate 24-hour variations in heart rate, cardiac conduction, refractoriness, ventricular repolarization, and the incidence of arrhythmogenic events for different types of cardiovascular diseases (Muller et al., 1989; Sarma et al., 1990; Schmidt et al., 1992; Kong et al., 1995; Tofler et al., 1995; Molnar et al., 1996; Venditti et al., 1996; Matsuo et al., 1999; Maron et al., 2009; Takigawa et al., 2012; Ruwald et al., 2015; Miyake et al., 2017). These time-of-day changes in cardiac electrophysiology reflect a combination of daily changes in endogenous physiological circadian rhythms, the environment, and behavior (Thosar et al., 2018; Delisle et al., 2021a). Understanding how daily changes in internal circadian rhythms, the environment, and behavior shape the 24-hour rhythms in normal cardiac electrophysiology and the incidence in arrhythmogenic events will facilitate the identification of new therapeutic strategies. This article focuses on emerging basic science studies that demonstrate how endogenous circadian mechanisms, as well as daily changes in the environment and behavior, contribute to 24-hour rhythms in cardiac electrophysiology.

Circadian Clocks in the Suprachiasmatic Nucleus Aligns Rhythms in Physiology and Behavior with the Light/Dark Cycle

Organisms evolved internal circadian rhythms that drive 24-hour rhythms in physiology and behavior in anticipation of predictable changes in the daily environment (Reppert & Weaver, 2002). In mammals, these physiological rhythms are initiated at the cellular level by the circadian clock mechanism, a transcription-translation feedback loop that normally cycles with a periodicity of 24 hours (Figure 1A). (Lowrey & Takahashi, 2004; Mohawk et al., 2012; Partch et al., 2014). The circadian clock mechanism is in most cells throughout the body, and it regulates 24-hour oscillations in gene expression, intracellular signaling, and membrane activity (Hastings et al., 2018; Harvey et al., 2020; Michel & Meijer, 2020). The positive limb of the circadian clock is activated by the heterodimerization of the basic helix-loop-helix transcription factors BMAL1 and CLOCK. BMAL1 and CLOCK directly increase the transcription of Period and Cryptochrome genes. PER (Period) and CRY (Cryptochrome) proteins negatively feedback to decrease the transcriptional activity of BMAL1 and CLOCK. As PER and CRY proteins are degraded, their repression of BMAL1 and CLOCK transcriptional activity decreases to repeat the cycle. In addition to this core loop, there are other feedback cycles and post-translational mechanisms that contribute to the circadian clock mechanism (Sato et al., 2004; Herzog et al., 2017). Therefore, circadian clocks are comprised of repeating feedback loops and cycles in both transcription and translation.

Figure 1. The circadian clock transcription translation feedback loop in the suprachiasmatic nucleus drives circadian rhythms.

Figure 1.

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A. A simplified schematic of the circadian clock mechanism. Heterodimerized BMAL1 and CLOCK transcription factors bind E-box (or E-box related) elements on promoters to activate transcription of core clock genes including Period (PER) and Cryptochrome (CRY). PER and CRY proteins dimerize and negatively feedback on BMAL1 and CLOCK activity. The circadian clock mechanism also regulates the tissue-specific expression of clock-controlled genes that are important in the regulation of physiology. Additional feedback loops that contribute to the circadian clock mechanism are not shown for simplicity. B. A schematic of a sagittal section of the mouse brain showing how light signals are transmitted to the SCN via the retinohypothalamic tract. The SCN signals nuclei in the hypothalamus to relay temporal information to neuroendocrine and brainstem autonomic nuclei. The inset shows an SCN neuron and the corresponding action potential (AP) firing frequency in the dark cycle (dark) and the light cycle (light). The SCN circadian clock regulates the rhythm in the AP firing frequency by altering membrane properties and ion channels by multiple regulatory mechanisms.

The circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus drives 24-hour rhythms in physiology and behavior that align the phase of the circadian clocks in the cells throughout the body (Kalsbeek et al., 2006). The circadian clocks in a subset of SCN neurons are entrained to the environment by light via the retinohypothalamic tract (Figure 1B). The light-entrained SCN neurons signal to the other SCN neurons and brain nuclei to align circadian rhythms in neurohumoral signaling (e.g., cortisol, catecholamines, melatonin), behavior (e.g., sleeping and eating), and physiology (heart rate, blood pressure, core body temperature) to the light cycle (Buijs & Kalsbeek, 2001; Hastings et al., 2018).

Circadian Clocks Regulate Membrane Excitability in the SCN

The circadian clocks in SCN neurons translate information about light cycles to the rest of the body by altering the phase of the intrinsic action potential (AP) firing frequency (Harvey et al., 2020). In nocturnal mice, the AP firing frequency in isolated SCN neurons is higher during the light portion of the cycle compared to the dark portion of the cycle. The cellular basis for the change in the firing frequency of APs at different times depends on changes in the membrane properties (i.e., ionic currents, membrane conductance, and membrane potential) that increase or decrease neuronal excitability (Hermanstyne et al., 2016; Hermanstyne et al., 2017; Harvey et al., 2020).

Studies show SCN neurons express several principal and auxiliary ionic currents that impact excitability (Harvey et al., 2020). Briefly, it is still not clear whether circadian clocks in SCN neurons impact AP firing frequency by modifying the temporal expression of a few principal currents or a large complement of secondary ionic currents (Meredith et al., 2006; Flourakis et al., 2015). It might be that daily changes in neuronal excitability are caused by changes in a few principal ionic currents, as well as several auxiliary ionic currents that support normal function (Harvey et al., 2020). Regardless, what is clear is that the circadian clock mechanism in the SCN regulates membrane excitability by altering the functional expression of ion channels through transcriptional and post-transcriptional mechanisms. Studies now show that circadian clocks in cardiomyocytes also regulate the expression of several principal and auxiliary cardiac ion channels important for sinoatrial nodal cell excitability and the cardiac action potential waveform (Figure 2A).

Figure 2. Cardiac ion channel genes are directly and indirectly regulated by the cardiomyocyte circadian clock mechanism.

Figure 2.

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A. Shown is a cartoon of a mouse electrocardiogram (ECG). The mouse ECG waveforms have distinct P, QRS, J, and T waves. The P wave is generated by the depolarization of the atrium, the QRS complex is generated by the depolarization of the ventricles, the J wave reflects early repolarization of the ventricle, and the T wave reflects delayed ventricular repolarization. Below the mouse ECG is a schematic showing a mouse ventricular action potential (AP) and principal (dark blue) and secondary (red) cardiac ion channel genes (proteins) that contribute to the ventricular AP waveform. Studies show that these genes exhibit a circadian oscillation in transcript levels. B. A simplified schematic of how the circadian clock mechanism can regulate the expression of cardiac ion channel genes. Heterodimerized BMAL1 and CLOCK transcription factors bind E-box (or E-box related) elements on promoters of ion channels genes (top, direct regulation) or transcription factor (TF) genes that regulate the transcription of cardiac ion channel genes (bottom, indirect regulation).

Cardiomyocyte Circadian Clocks Regulate Cardiac Ion Channel mRNA Transcript levels

As noted above, circadian clocks regulate the rhythmic expression of mRNA transcript levels. In the mouse heart, approximately 15% of myocardial mRNA transcript levels and 8% of the sampled proteome change across the 24-hour light and dark cycle (Storch et al., 2002; Martino et al., 2004; Martino & Sole, 2009; Podobed et al., 2014; Zhang et al., 2014). Many of these rhythmically expressed mRNA transcripts map to important biological pathways, including gene transcription, protein translation, mitochondrial respiration, signaling pathways, growth, and cellular/tissue remodeling. A subset of rhythmically expressed mRNA transcripts is directly driven by the cardiomyocyte circadian clock mechanism. Early data from rat hearts suggest that at least some of the cycling mRNA transcripts encode cardiac ion channels important for repolarization. Yamashita and colleagues tested whether the mRNA levels of several different cardiac ion channel mRNA transcript levels oscillate across 12-hour light and dark cycles. They found that the mRNA transcript levels for two voltage-gated K+ channels (Kcna5 and Kcnd2) oscillated with a periodicity of 24-hours (Yamashita et al., 2003). Kcna5 encodes the pore-forming Kv1.5 channel protein and Kcnd2 encodes the pore-forming Kv4.2 channel protein (Figure 2A) (Nerbonne, 2014). Interestingly, the phases for the oscillations in the levels of mRNA transcripts for Kcna5 and Kcnd2 were inverted with respect to one another. The oscillation in the levels of Kcna5 mRNA transcript peaked during the dark cycle (active phase), and the oscillation in the levels of Kcnd2 mRNA transcript levels peaked during the light cycle (inactive phase). The change in K+ channel mRNA transcript levels correlated with time-of-day changes in the level of the Kv1.5 and Kv4.2 channel proteins, electrophysiological characteristics in cardiomyocytes (macroscopic K+ currents), and changes in the response of cardiac refractoriness to pharmacological block of K+ currents. Although the Kcna5 and Kcnd2 K+ channel mRNA transcript levels oscillated with a periodicity of 24-hours, it was unclear as to whether the oscillation in mRNA transcript levels depended on extrinsic neurohumoral signaling or the cardiomyocyte circadian clock.

Subsequent studies used established chronobiological approaches to investigate whether the endogenous circadian clock mechanism in the heart regulates the mRNA expression of the different ion channel genes (Jeyaraj et al., 2012; Schroder et al., 2013; Young et al., 2014; Schroder et al., 2015; Chen et al., 2016; D'Souza et al., 2021; Gottlieb et al., 2021; McTiernan et al., 2021). These studies determined the mRNA transcript levels for several different ion channels cycled with an intrinsic 24-hour rhythm by measuring mRNA levels in constant dark or “free-running” conditions. The studies found that, in mouse hearts, the mRNA transcript levels for Kcnd2, Kcnip2, Kcnh2, Kcnq1, Kcnj2, Hcn4, and Scn5a cycled with a periodicity of 24-hours in free running conditions (Figure 2A) (Jeyaraj et al., 2012; Schroder et al., 2013; Zhang et al., 2014; Schroder et al., 2015; Schroder et al., 2021b). To investigate the role that the cardiomyocyte circadian clock has on the transcriptional regulation of these ion channels, the circadian oscillation in mRNA transcript levels was studied using transgenic mouse models that disrupt cardiomyocyte circadian clock signaling by Bmal1 knockout or deletion. The different types of transgenic mice used in these studies include the germline Bmal1 knockout (Bmal1−/−) mice (Bunger et al., 2000), the cardiomyocyte specific Bmal1 knockout (CBK) mice (Young et al., 2014), and mice that allow for inducing the cardiomyocyte specific deletion of Bmal1 (iCSΔBmal1) in adult mouse hearts (Schroder et al., 2013). Data from these studies show that the circadian oscillation in Kcnip2 mRNA transcript levels were reduced in Bmal1−/− mice, and the circadian oscillation and mRNA transcript levels in Kcnh2, Kcnq1, Kcnj2, Hcn4 and Scn5a mRNA were lost and reduced in iCSΔBmal1 mice after inducing the deletion of Bmal1 (iCSΔBmal1−/−) (Jeyaraj et al., 2012; Schroder et al., 2013; Schroder et al., 2015; Schroder et al., 2021b). These studies confirmed that the core circadian clock mechanism in cardiomyocytes regulates cellular ion channel mRNA levels.

Cardiomyocyte Circadian Clocks Regulate Cardiac Ion Channels Expression by Multiple Mechanisms

Jeyaraj and colleagues first linked the cardiomyocyte circadian clock with the functional regulation of cardiac channel expression (Jeyaraj et al., 2012). They found that the mRNA transcript levels for the Klf15 (Krüppel-like factor 15) showed an endogenous circadian oscillation in mouse hearts. Microarray data of mouse hearts deficient in Klf15 suggested that KLF15 regulates the transcription of the K+ channel subunit Kcnip2. Kcnip2 encodes KChIP2 (K+ channel interacting protein 2), which regulates the function of the Kv4.2 channel proteins. They demonstrated that BMAL1 directly regulated the circadian expression of Klf15 mRNA transcript levels and KLF15 associated with the Kcnip2 promoter. Mice deficient in Klf15 showed a reduction in Kcnip2 mRNA levels, a decrease in time-of-day changes in KChiP2 protein levels, and a reduction in cardiac K+ currents. The data helped to identify a mechanism whereby the cardiomyocyte circadian clock indirectly impacts cardiac ion channel mRNA expression in the heart. In this case, circadian clock transcription factors regulated the expression of transcription factors that modified the expression of a cardiac ion channel gene (Figure 2B). This type of indirect regulation by the circadian clock may contribute to the regulation of other cardiac ion channel genes. Studies show the cardiomyocyte circadian clock mechanism is important for the expression of additional cardiac transcription factors (e.g., Tbx5 and Gata4) important for normal cardiac ion channel expression (Arnolds et al., 2012; Tarradas et al., 2017).

A more direct role for the circadian clock regulation of cardiac ion channel expression was proposed for the cardiac ion channel genes Scn5a and Kcnh2 (Schroder et al., 2013; Schroder et al., 2015). Scn5a encodes the pore-forming subunit of the voltage-gated cardiac Na+ channel Nav1.5 and Kcnh2 encodes the pore-forming subunit of the voltage-gated K+ channel Kv11.1. The free running 24-hour oscillation in the mRNA transcript levels for these proteins was lost in the hearts of iCSΔBmal1−/− mice, and ventricular cardiomyocytes isolated from these mice had smaller macroscopic INa and IKr. Heterologous expression assays designed to assess human promoter activity using cloned SCN5A or KCNH2 promoters that drive the expression of luciferase demonstrated that the SCN5A or KCNH2 promoters were transactivated by overexpression of BMAL1 and CLOCK, and the SCN5A and KCNH2 promoters showed circadian luciferase activity in cells using real-time bioluminescence recordings (Schroder et al., 2013; Schroder et al., 2015; Delisle et al., 2021c).

More recently, studies demonstrated that the circadian clock mechanism in mouse sinoatrial nodal cells regulated the expression of the Hcn4 mRNA transcript levels (D'Souza et al., 2021). There was a loss in the time-of-day difference in Hcn4 mRNA transcript and protein levels in CBK mouse hearts. Bioluminescence recordings utilizing cloned human HCN4 promoter luciferase reporter constructs showed that the HCN4 promoter exhibited circadian luciferase promoter activity in vitro. Together, the data suggest a working model whereby the cardiomyocyte circadian clock mechanism can directly regulate the expression of several different cardiac ion channel genes in both the working and autorhythmic myocardium (Figure 2B).

There are discrepancies between animal studies as to which cardiac ion channel mRNA transcripts have a circadian oscillation. Some possible reasons for these discrepancies include differences in the design of the study, the strain/species differences, collection environment, the precision of the measurements, the total time course of the study, and the statistical method or algorithm used to detect rhythmic changes. To conclude whether mRNA transcripts have an endogenous circadian oscillation, samples should be collected in free running conditions, at a high frequency (e.g., every few hours), for more than one day, and analyzed using a robust statistical method or algorithm.

Caution is also needed for extrapolating results in animal and cell models to humans. Human studies on the endogenous circadian regulation of cardiac electrophysiology remain challenging because cardiac tissue can only be collected under limited circumstances (e.g., transplant, brain death, etc.). However, McTiernan and colleagues were able to quantify the changes in ventricular mRNA transcript levels isolated from ventricular tissue taken from people with heart failure undergoing transplant. Plotting the mRNA transcript levels relative to the sunrise demonstrated 24-hour rhythms in the mRNA levels for core clock genes and several cardiac ion channels (McTiernan et al., 2021). These human data, in combination with data from the cloned human ion channel promoter studies, suggest the circadian clock regulation of cardiac ion channel gene expression and mRNA transcript levels may be conserved.

The studies outlined above suggest that the cardiomyocyte circadian clock mechanism indirectly and directly regulates the circadian expression of cardiac ion channel mRNA transcripts. However, circadian oscillations in cardiac ion channel mRNA transcript levels may generate daily oscillations in channel proteins or ionic currents. One reason is many ion channel proteins have relatively long half-lives, and as such, circadian oscillations in mRNA levels may primarily impact steady-state levels in ion channel proteins (Mauvoisin et al., 2014). Even if circadian oscillations in ion channel mRNA transcript levels translate to oscillations in ion channel protein levels, the changes in channel protein levels do not necessarily impact ionic current at the cell surface membrane. Several additional post-transcriptional processes can directly impact the number of ion channel proteins in the cell surface membrane, open channel probability, and single channel current. These post-transcriptional processes include changes in channel translation, transport to and from the cell surface membrane, modification by cell signaling messengers, and degradation. Although the role that circadian clock regulation has on 24-hour oscillations in ionic currents, hearts isolated from mice housed in 12-hour light and dark cycles at different times show clear time-of-day changes in cellular electrophysiology, including a shorter AP duration, a decrease in the frequency of spontaneous premature ventricular contractions, and a decrease in pacing induced arrhythmias shortly after the start of the dark cycle (Wang et al., 2020). Future studies designed to determine the role that the cardiomyocyte circadian clock has in ex vivo time-of-day changes cardiac electrophysiology are needed.

The 24-hour Rhythm in Heart Rate is Primarily Driven by Signaling from the SCN and the Autonomic Nervous System

The roles of circadian clocks, the SCN, and autonomic activity in generating the 24-hour rhythm in heart rate and cardiac electrophysiology in vivo are now becoming clear. Autonomic nerve and adrenal activity modifies the firing frequency of the sinoatrial node by membrane receptor mediated mechanisms to increase or decrease heart rate (Figure 3) (Monfredi & Lakatta, 2019). Electrocardiographic (ECG) telemetry studies in rats and mice show that the average heart rate and QT-interval follow a 24-hour rhythm in 12-hour light and dark cycles and free running conditions (Schroder et al., 2013; D'Souza et al., 2021; Gottlieb et al., 2021; Hayter et al., 2021).

Figure 3. The SCN and autonomic nervous system are the primary drivers for generating circadian and 24-hour rhythms in heart rate and ventricular repolarization.

Figure 3.

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A. Signaling from the SCN and autonomic nervous system mediate sympathetic and parasympathetic signaling to the heart to drive circadian and 24-hour rhythms. Shown is a simplified schematic connecting efferent mechanisms regulating the heart originating from higher brain centers, the brain stem, spinal cord, extracardiac-intrathoracic ganglia and the adrenal medulla. Not shown are afferent pathways that can relay sensory information. Autonomic blockade and sinoatrial node isolation reveal a smaller time-of-day differences in intrinsic beating rate that is lost in CBK mice. B. Disrupting the cardiomyocyte circadian clock mechanism in adult mouse hearts does not disrupt the 24-hour rhythm in heart rate or ventricular repolarization. Shown is summary of electrocardiographic (ECG) data recorded from mice using telemetry for ≈3 days. The hourly RR- or uncorrected QT-intervals were plotted as a function of Zeitgeber Time (ZT), where ZT 0 is the start of the 12-hour light phase. The data for control (solid circles) and iCSΔBmal1−/− (open squares) mice are shown. The shaded and light regions represent dark and light, respectively. The grey line is a non-linear sinusoidal fit to the data. These data are reprinted from with permission from Elsevier see (Schroder et al., 2015) for article details.

Scheer and colleagues demonstrated that the circadian rhythm in heart rate is lost in SCN-lesioned rats. The authors identified multi-synaptic connections between the SCN and brain nuclei that are important for autonomic function (e.g., the paraventricular nucleus) (Scheer et al., 2001). Tong and colleagues also demonstrated that the 24-hour rhythm in heart rate is lost in SCN-lesioned mice (Tong et al., 2013). They found that inhibiting the activation of the beta-adrenergic and muscarinic receptors mimicked the effects of SCN-lesioning and caused a loss in the 24-hour rhythm of heart rate. However, subsequent studies in mice found that the intrinsic heart rate (i.e., the heart rate measured when autonomic signaling to the sinoatrial node is inhibited or lost) still showed a small but significant time-of-day difference (Hayter et al., 2021). The cardiomyocyte circadian clock appears to be important for generating the time-of-day difference in intrinsic heart rate because it was lost in CBK mice. The mechanism with which the cardiomyocyte circadian clock contributes to the time-of-day differences in intrinsic heart rate may reflect time-of-day changes in ionic currents (e.g., the funny current) important for sinoatrial node pacemaker activity (D'Souza et al., 2021; Hayter et al., 2021). Data also suggest that the circadian clock might contribute to a time-of-day difference in the intrinsic heart rate by generating rhythmic changes in intracellular Na+ and K+ content in sinoatrial nodal cells (Stangherlin et al., 2021).

What is clear is the cardiomyocyte circadian clock mechanism is not obligatory for generating a 24-hour or circadian rhythm in heart rate in vivo. Gottlieb and colleagues compared 24-hour rhythms in the average heart rates of control and CBK mice (Gottlieb et al., 2021). They demonstrated that, although the 24-hour average in heart rate is slower in CBK mice, the 24-hour rhythm in heart rate was preserved in CBK mice housed in 12-hour light and dark cycles or free running conditions. These findings confirmed similar observations seen in the inducible iCSBmal1−/− mice (Schroder et al., 2015). iCSΔBmal1−/− mice had a similar 24-hour rhythms in heart rate compared to control mice (Figure 3B) (Schroder et al., 2013). However, the difference in the 24-hour average in heart rate between control and iCSΔBmal1−/− mice was less obvious than CBK mice. Regardless, the results from the studies in SCN lesioned rats and mice, as well as the studies in CBK and iCSΔBmal1−/− mice, suggest the 24-hour rhythm in heart rate is primarily driven by autonomic receptor-mediated mechanisms originating from the SCN and not the cardiomyocyte circadian clock (Monfredi & Lakatta, 2019).

The Cardiomyocyte Circadian Clock Buffers Against QT-interval Prolongation

The timing of ventricular repolarization can be measured from the beginning of the QRS complex to the end of the T-wave (the QT-interval) (Mitchell et al., 1998). The duration of the QT-interval depends on the preceding RR-interval, such that, as the RR-interval becomes longer or shorter, the QT-interval will become longer and shorter. Abnormally long or short QT-intervals associate with an increased risk for deadly ventricular arrhythmias (Postema & Wilde, 2014). Several studies show that, compared to control mice, the QT-interval was longer in CBK and iCSΔBmal1−/− mice independent of the heart rate (Schroder et al., 2015; Gottlieb et al., 2021; Schroder et al., 2021b). A cellular surrogate of the QT-interval is the duration of the ventricular AP waveform (Figure 2A). Similar to the QT-interval, the duration of the cardiac AP waveform depends on the preceding cycle length between AP waveforms. Studies measuring ventricular APs in isolated control and CBK hearts found that, when the hearts were electrically paced at a constant cycle length, the CBK hearts had a longer ventricular AP waveform and shallower repolarizing slope (Gottlieb et al., 2021). Therefore, the prolongation in the QT-interval in the CBK mice likely reflects a decrease in key K+ currents that drive ventricular repolarization (Figure 2A).

Although the QT-interval normally changes with heart rate, a disproportionate increase in the duration of the QT-interval as a function of heart rate is pro-arrhythmic (Merri et al., 1992; Schroder et al., 2014). Data show that the difference in the QT-interval between control and iCSBmal1−/− mice increased at slower heart rates (Figure 3B) (Schroder et al., 2015; Schroder et al., 2021b). In other words, the QT-interval became disproportionately longer in iCSΔBmal1−/− mice as the heart rate became slower. The disproportionate prolongation in the QT-interval at slower heart rates caused an increase in the amplitude in the 24-hour rhythm of the QT-interval compared to control mice (Schroder et al., 2013). In other words, disrupting the cardiomyocyte circadian clock mechanism increased the amplitude in the 24-hour rhythm in the QT-interval. This result unmasks the complexity of how circadian clock disruption in the heart can translate to larger 24-hour rhythms in cardiac repolarization. These results suggest that a functional role for the cardiomyocyte circadian clock is to regulate ion channel function to buffer the responsivity of the heart against 24-hour changes in neurohumoral signaling.

Environmental and Behavioral Contributions to Daily Rhythms in Heart Rate and Ventricular Repolarization

The 24-hour rhythm in heart rate is primarily driven by autonomic receptor-mediated mechanisms originating from the SCN (Figures 1B and 4). So, what happens to heart rate and cardiac electrophysiology when the environmental light cycle is altered? Studies using mice housed non-24-hour light and dark cycles (11.25-hour light and dark cycles, instead of 12-hour light and dark cycles) demonstrated that the daily rhythms in RR-, PR-, and QT-intervals were disrupted, and there was an overall slowing in the RR-, PR-, QT-intervals (West et al., 2017). Studies that simulate jetlag by advancing the light cycle also showed acute disruptions in cardiac electrophysiology (Hayter et al., 2021). An abrupt advancement in the light cycle by 9 hours caused a temporary misalignment between the 24-hour rhythms in the RR-interval and PR-segment (a measure of atrioventricular conduction). The phase in the 24-hour rhythm in the RR-interval quickly realigned to the new light and dark cycle, but the phase in the 24-hour rhythm in the PR-segment did not. It took several days for the PR-segment to realign with the advanced light cycle. Experiments suggested that one possible mechanism for faster realignment in the 24-hour rhythm of the RR-interval to the advanced light cycle was related to how the cardiomyocyte circadian clock impacts sinoatrial node excitability.

Daily rhythms in physiological behavior also play an important role in shaping 24-hour rhythms in cardiac electrophysiology. Studies show that the amplitude in the 24-hour rhythm of the heart rate in mice increased with exercise activity (wheel running) (Barazi et al., 2021). Also, studies that restrict the timing of feeding behavior of mice to the light cycle (which is inverted to their normal feeding pattern) for several weeks increased the 24-hour rhythm amplitudes and means for the RR- and QT-intervals (Schroder et al., 2014). Time restricted feeding to the light cycle also caused a large shift in the phase of the 24-hour rhythms of the RR- and QT-intervals by 15 hours. Time restricted feeding to the light cycle had a similar effect on the 24-hour rhythms in the RR- and QT-intervals measured from iCSBmal1−/− mice, suggesting that the impact time restricted feeding has on cardiac electrophysiology was independent of the cardiomyocyte circadian clock mechanism (Schroder et al., 2021a). The time restricted feeding studies are exciting because they highlight an underrecognized association between feeding behavior and 24-hour rhythms in cardiac electrophysiology.

Summary

Studies suggest that the SCN circadian clock mechanisms generates a daily oscillation in the AP firing frequency by altering the membrane properties and several ionic currents through transcriptional, translational, and post-translational mechanisms. Cardiomyocytes possess circadian clocks that also regulate the functional expression of different ion channels. Thus far, most studies show that the cardiomyocyte circadian clock mechanism directly and indirectly regulates the circadian expression of a subset of ion channel mRNA transcripts. Genetic mouse models that disrupt the cardiomyocyte circadian clock mechanism by deletion of Bmal1 show a loss in the circadian expression of several ion channel transcripts and corresponding ionic currents. Future studies are needed to determine if the cardiomyocyte circadian clock can regulate the functional expression of cardiac ion channels by additional post-transcriptional mechanisms.

Several studies suggest that the circadian and 24-hour rhythm in heart rate is driven by signaling from the SCN and the autonomic nervous system. However, more recent work has identified a role for the cardiomyocyte circadian clock contributing to a daily change in the intrinsic heart rate. The cardiomyocyte circadian clock mechanism limits QT-interval prolongation, especially as slow heart rates. The regulation of the QT-interval by the cardiomyocyte circadian clock appears to be secondary to the regulations of K+ currents that are important for the repolarization of the ventricular AP waveform. Paradoxically, the disruption of the cardiomyocyte circadian clock mechanism in cardiomyocytes causes a disproportionate increase in the amplitude of the 24-hour rhythm in the QT-interval.

Daily changes in the environment and behavior also contribute to the 24-hour rhythms in heart rate, cardiac conduction, and ventricular repolarization. Experimental models that alter the duration of the light and dark cycles, simulate jetlag, increase exercise, or alter feeding behavior all showed impacts on the 24-hour rhythms in cardiac electrophysiology. These results are particularly important considering the link between circadian rhythm disruption, cardiovascular disease, and sudden cardiac death (Muller et al., 1989; Thosar et al., 2018).

Animal models have helped us to better understand how endogenous circadian mechanism, as well as daily rhythms in the environment and behavior, each impact 24-hour rhythms in cardiac electrophysiology. Additional studies translating this work in people are needed, but these studies suggest that targeting endogenous circadian mechanisms, as well as modifying the timing of environmental signals and behavior, could lead to additional therapeutic strategies that can mitigate arrhythmogenic risk in people with different types of heart disease (Tsimakouridze et al., 2015; Delisle et al., 2021a, b; van Weperen et al., 2021).

Acknowledgement

Biorender was used to generate some of the figures.

Funding

This work was supported by National Heart Lung and Blood Institute grants R01HL153042 and R01HL141343.

Footnotes

Competing interest statement

None.

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