Circadian rhythms in physiology and behavior are ≈24-hour biological cycles regulated by internal biological clocks (ie, circadian clocks) that optimize organismal homeostasis in response to ...predictable environmental changes. These clocks are present in virtually all cells in the body, including cardiomyocytes. Many decades ago, clinicians and researchers became interested in studying daily patterns of triggers for sudden cardiac death, the incidence of sudden cardiac death, and cardiac arrhythmias. This review highlights historical and contemporary studies examining the role of day/night rhythms in the timing of cardiovascular events, delves into changes in the timing of these events over the last few decades, and discusses cardiovascular disease-specific differences in the timing of cardiovascular events. The current understanding of the environmental, behavioral, and circadian mechanisms that regulate cardiac electrophysiology is examined with a focus on the circadian regulation of cardiac ion channels and ion channel regulatory genes. Understanding the contribution of environmental, behavioral, and circadian rhythms on arrhythmia susceptibility and the incidence of sudden cardiac death will be essential in developing future chronotherapies.
Sudden cardiac death (SCD) follows a diurnal variation. Data suggest the timing of SCD is influenced by circadian (~24-hour) changes in neurohumoral and cardiomyocyte-specific regulation of the ...heart's electrical properties. The basic helix-loop-helix transcription factors brain muscle arnt-like1 (BMAL1) and circadian locomotor output control kaput (CLOCK) coordinate the circadian expression of select genes.
We sought to test whether Bmal1 expression in cardiomyocytes contributes to K(+) channel expression and diurnal changes in ventricular repolarization.
We used transgenic mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1(-/-)). We used quantitative polymerase chain reaction, voltage clamping, promoter-reporter bioluminescence assays, and electrocardiographic telemetry.
Although several K(+) channel gene transcripts were downregulated in iCSΔBmal1(-/-)mouse hearts, only Kcnh2 exhibited a robust circadian pattern of expression that was disrupted in iCSΔBmal1(-/-) hearts. Kcnh2 underlies the rapidly activating delayed-rectifier K(+) current, and the rapidly activating delayed-rectifier K(+) current recorded from iCSΔBmal1(-/-) ventricular cardiomyocytes was ~50% smaller than control ventricular myocytes. Promoter-reporter assays demonstrated that the human Kcnh2 promoter is transactivated by the coexpression of BMAL1 and CLOCK. Electrocardiographic analysis showed that iCSΔBmal1(-/-) mice developed a prolongation in the heart rate-corrected QT interval during the light (resting) phase. This was secondary to an augmented circadian rhythm in the uncorrected QT interval without a corresponding change in the RR interval.
The molecular clock in the heart regulates the circadian expression of Kcnh2, modifies K(+) channel gene expression, and is important for normal ventricular repolarization. Disruption of the cardiomyocyte circadian clock mechanism likely unmasks diurnal changes in ventricular repolarization that could contribute to an increased risk of cardiac arrhythmias/SCD.
Daily variations in cardiac electrophysiology and the incidence for different types of arrhythmias reflect ≈24 h changes in the environment, behaviour 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 behaviour, have on 24 h 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 h. Several studies now show that 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 h rhythms in heart rate and ventricular repolarization are primarily driven by autonomic signalling. 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 h rhythm in heart rate to abrupt changes in the light cycle. Additional studies show that modifying rhythmic behaviours (including feeding behaviour) can dramatically impact the 24 h rhythms in heart rate and ventricular repolarization. If these mechanisms are conserved, these studies suggest that targeting endogenous circadian mechanisms in the heart, as well as modifying the timing of certain rhythmic behaviours, could emerge as therapeutic strategies to support heart function against perturbations and regulate 24 h rhythms in cardiac electrophysiology.
figure legend Time‐of‐day variations in cardiac electrophysiology and the incidence of arrhythmogenic events are generated by endogenous circadian rhythms, 24 h rhythms in the environment and 24 h rhythms in behaviour. This article focuses on studies that use animal models to separate the impact that circadian clocks (ubiquitously expressed transcription–translation feedback loops that initiate circadian rhythms), daily changes in the light cycle and daily changes in the timing of feeding have on 24 h rhythms in cardiac electrophysiology. Studies now show that the circadian clock mechanism in the heart regulates the expression of cardiac ion channels; underlies time‐of‐day changes in intrinsic sinoatrial node excitability; and shapes the ventricular action potential waveform. Additional studies show that modifying the light cycle and rhythmic feeding behaviour can dramatically impact the 24 h rhythms in cardiac electrophysiology. If conserved, these studies suggest that targeting endogenous circadian clock mechanisms in the heart, as well as modifying 24 h rhythms in the environment and behaviour, could emerge as therapeutic strategies to support normal cardiac electrophysiology and mitigate the risk of arrhythmogenic events.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization ...of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano-Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in
(LQT1) and
(LQT2). We move beyond the "benign" to a "pathogenic" binary classification scheme for different
and
missense variants and discuss gene- and mutation-specific differences in K
channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of
and
variants, with the goal of realizing a layered precision medicine approach focused on individuals.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract The molecular mechanisms underlying congenital long QT syndrome (LQTS) are now beginning to be understood. New insights into the etiology and therapeutic strategies are emerging from ...heterologous expression studies of LQTS-linked mutant proteins, as well as inducible pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from LQTS patients. This review focuses on the major molecular mechanism that underlies LQTS type 2 (LQT2). LQT2 is caused by loss of function (LOF) mutations in KCNH2 (also known as the human Ether-à-go-go-Related Gene or hERG ). Most LQT2-linked mutations are missense mutations and functional studies suggest that ~90% of them disrupt the intracellular transport (trafficking) of KCNH2 -encoded Kv11.1 proteins to the cell membrane. Trafficking deficient LQT2 mutations disrupt Kv11.1 protein folding and misfolded Kv11.1 proteins are retained in the endoplasmic reticulum (ER) until they are degraded in the ER associated degradation pathway (ERAD). This review focuses on the quality control mechanisms in the ER that contribute to the folding and ERAD of Kv11.1 proteins; the mechanism for ER export of Kv11.1 proteins in the secretory pathway; different subclasses of trafficking deficient LQT2 mutations; and strategies being developed to mitigate or correct trafficking deficient LQT2-related phenotypes.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, VSZLJ, ZAGLJ, ZRSKP
The graphic symbolizes the well-known observation that cardiac electrophysiology changes at different times of day. Clinically, sudden cardiac death is shown to have a time of day increase incidence ...for certain types of heart disease. To better understand how environment and gene interactions contribute to cardiac electrophysiology, several investigators have generated transgenic mouse models that disrupt circadian clocks in different tissues including the heart. These studies show a role for functional circadian clocks in regulating heart rate, the development of dilated cardiomyopathy, cardiac repolarization, and cardiac ion channels.
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Daily changes in the incidence of sudden cardiac death (SCD) reveal an interaction between environmental rhythms and internal circadian rhythms. Circadian rhythms are physiological rhythms that alter physiology to anticipate daily changes in the environment. They reflect coordinated activity of cellular circadian clocks that exist throughout the body. This review provides an overview of the state of the field by summarizing the results of several different transgenic mouse models that disrupt the function of circadian clocks throughout the body, in cardiomyocytes, or in adult cardiomyocytes. These studies identify important roles for circadian clocks in regulating heart rate, ventricular repolarization, arrhythmogenesis, and the functional expression of cardiac ion channels. They highlight a new dimension in the regulation of cardiac excitability and represent initial forays into understanding the complexities of how time impacts the functional regulation of ion channels, cardiac excitability, and time of day changes in the incidence of SCD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rhythmic feeding behavior is critical for regulating phase and amplitude in the »24-hour variation of heart rate (RR intervals), ventricular repolarization (QT intervals), and core body temperature ...in mice. We hypothesized changes in cardiac electrophysiology associated with feeding behavior were secondary to changes in core body temperature. Telemetry was used to record electrocardiograms and core body temperature in mice during ad libitum-fed conditions and after inverting normal feeding behavior by restricting food access to the light cycle. Light cycle-restricted feeding modified the phase and amplitude of 24-hour rhythms in RR and QT intervals, and core body temperature to realign with the new feeding time. Changes in core body temperature alone could not account for changes in phase and amplitude in the »24-hour variation of the RR intervals. Heart rate variability analysis and inhibiting β-adrenergic and muscarinic receptors suggested that changes in the phase and amplitude of 24-hour rhythms in RR intervals were secondary to changes in autonomic signaling. In contrast, changes in QT intervals closely mirrored changes in core body temperature. Studies at thermoneutrality confirmed that the daily variation in QT interval, but not RR interval, primarily reflected daily changes in core body temperature (even in ad libitum-fed conditions). Correcting the QT interval for differences in core body temperature helped unmask QT interval prolongation after starting light cycle-restricted feeding and in a mouse model of long QT syndrome. We conclude feeding behavior alters autonomic signaling and core body temperature to regulate phase and amplitude in RR and QT intervals, respectively.
Cardiac electrophysiological studies demonstrate that restricting the feeding of mice to the light cycle (time restricted feeding or TRF) causes a pronounced change in heart rate and ventricular ...repolarization as measured by the RR- and QT-interval, respectively. TRF slows heart rate and shifts the peak (acrophase) of the day/night rhythms in the RR- and QT-intervals from the light to the dark cycle. This study tested the hypothesis that these changes in cardiac electrophysiology are driven by the cardiomyocyte circadian clock mechanism. We determined the impact that TRF had on RR- and QT-intervals in control mice or mice that had the cardiomyocyte circadian clock mechanism disrupted by inducing the deletion of Bmal1 in adult cardiomyocytes (iCSΔBmal1
−/−
mice). In control and iCSΔBmal1
−/−
mice, TRF increased the RR-intervals measured during the dark cycle and shifted the acrophase of the day/night rhythm in the RR-interval from the light to the dark cycle. Compared to control mice, TRF caused a larger prolongation of the QT-interval measured from iCSΔBmal1
−/−
mice during the dark cycle. The larger QT-interval prolongation in the iCSΔBmal1
−/−
mice caused an increased mean and amplitude in the day/night rhythm of the QT-interval. There was not a difference in the TRF-induced shift in the day/night rhythm of the QT-interval measured from control or iCSΔBmal1
−/−
mice. We conclude that the cardiomyocyte circadian clock does not drive the changes in heart rate or ventricular repolarization with TRF. However, TRF unmasks an important role for the cardiomyocyte circadian clock to prevent excessive QT-interval prolongation, especially at slow heart rates.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous ...expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the
gene (also known as the human ether-à-go-go-related gene or
). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the
-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which
missense variants confer a high-risk for LQT2.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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