Download Minding the gaps that link intrinsic circadian clock within the heart to

Am J Physiol Cell Physiol 304: C941–C944, 2013;
doi:10.1152/ajpcell.00072.2013.
Editorial Focus
Minding the gaps that link intrinsic circadian clock within the heart to its
intrinsic ultradian pacemaker clocks. Focus on “The cardiomyocyte molecular
clock, regulation of Scn5a, and arrhythmia susceptibility”
Edward G. Lakatta, Yael Yaniv, and Victor A. Maltsev
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of
Health, Baltimore, Maryland
Life Emerges From Functions of a System of Synchronized
Clocks
The Hierarchy of Clocks Within the Heart
Cardiovascular function is regulated by a complex hierarchical
clock system. Circadian regulation contributes to normal heart
function. Disruption of circadian clocks within mice leads to
cardiac pathology that includes reductions in heart rate, beating
rate variability (1), arrhythmias, altered substrate metabolism and
contractile function (2), and altered adaptations of the heart in
response to hypertrophic stimuli (6). Circadian patterns of regulation of Ca2⫹ channel subunits and Ca2⫹ current densities and
phosphorylation of key signaling molecules, including ERK, p38,
Akt, and GSK, have been identified (7).
A hierarchy of ultradian clocks within the heart regulates
beat-to-beat cardiac function (12). Synchronization of these
“local” clocks over short time scales in different parts of the
heart ensures the rhythmic generation and execution of each
heartbeat (Fig. 1): The “period” of clocks within the sinoatrial
node (SAN) pacemaker cell from which impulses emerge that
initiate each heart beat is synchronized with the periods of the
other parts of the electrical system that conduct the impulse to
the ventricular myocardium to elicit a synchronized contraction
of ventricular myocytes that is required to eject blood from the
heart. Regulation of heart rate and rhythm by the hierarchical
clock system is modulated by autonomic signaling from the
brain via neurotransmitter release from the vagus and sympaAddress for reprint requests and other correspondence: E. G. Lakatta,
Laboratory of Cardiovascular Science, Intramural Research Program, National
Institute on Aging, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825
(e-mail: [email protected]).
http://www.ajpcell.org
There Is a Formidable Gap in Knowledge About How
Functions of Cardiac Circadian Clock Link to Those of
Cardiac Ultradian Clocks
In this issue of American Journal of Physiology-Cell Physiology, Schroder et al. (15) bridged this gap by investigating
cardiac clock mechanisms in vivo and in vitro in adult ventricular cardiomyocytes by 1) a deletion of the cardiac clock
gene Bmal1 in adult mice and 2) assessing the effect of this
deletion on heart rate and rhythm in mice and in isolated
cardiomyocytes. The diurnal pattern of heart rate observed in
wild-type (WT) mice was suppressed in Bal1-/- mice. In
addition to this altered circadian heart rhythmicity, Shroder et
al. observed changes in ultradian clocks that regulate beat-tobeat function: 1) a reduction in the rate and disruption of the
rhythm at which impulses emanate from the SAN, manifested
by prolonged and dysrhythmic R-R intervals on the ECG (Fig.
1); and 2) abnormal spread of impulse conduction across the
ventricle, i.e.,prolonged QRS complex on the ECG (Fig. 1).
Schroder et al. screened circadian expression profiles of
genes known to be involved in regulation of heart beating rate
and rhythm. They observed that Scn5a, which codes Nav1.5,
the major subunit of cardiac-type Na⫹ channels (i.e., those that
generate Na⫹ current, INa), exhibited diurnal expression in WT
hearts, but this pattern was suppressed in hearts of Bmal1-/mice. But how is the altered diurnal expression of Scn5a, i.e.,
a long oscillatory period, in Bmal1-/- mice coupled to abnormalities in ultradian clock phenotypes of the cardiac electrical
impulse initiation and conduction? A clue to the link between
circadian and ultradian abnormalities produced by the cardiacspecific disruption of the Bmal1-/- gene is that Schroder et al.
observed that not only is the cardiac diurnal expression of
pattern of Scn5a (i.e., Nav1.5 transcript) disturbed in Bmal1-/-,
but also Bmal1-/- hearts have reduced 1) Nav1.5 protein expression and 2) ad hoc peak INa amplitude density in their
ventricular myocytes. The authors note that the Bmal1-/- phenotype is strikingly similar to that of mice with targeted
disruption of Scn5a, in which INa was reduced by 50% (13).
This suggests that one mechanism that links circadian to
ultradian cardiac clocks is rhythmic change in transcription,
C941
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A hierarchical system of clocks within cells throughout the
body creates and synchronizes rhythmic functions from which
life emerges. Biological circadian rhythms, linked to light and
darkness in an organism’s environment, are generated by
transcription-translation feedback mechanisms on universal
“core” clock genes, e.g., Clock, Bmal1, Per1, Per2, Cry1 and
Cry2 (16). Clocks within the brain broadcast signals to all
tissues (5). Many cell types also exhibit their “local” circadian
clocks, as well as infradian and ultradian clocks that rhythmically regulate cell type-specific functions on time scales commensurate with the functions. Functional regulation by clocks
range from activation-inactivation-reactivation cycles of molecules (e.g., ion channels) at millisecond scales, the heart’s
beating at cycles of hundreds of milliseconds, respiration at
cycle of seconds, low-frequency autonomic signaling at cycles
of tens of seconds, to diurnal and infradian variations of
numerous body functions.
thetic nerves (Fig. 1). Desynchronization of brain-heart clock
functions or of any clock periods within and among different
cardiac cell types leads to abnormalities in impulse initiation
by SAN cells, in conduction of the impulse, and to abnormalities of cardiac contraction. Interaction and spread of electrical
excitation across cell types of the hierarchical clock system
(brain to ventricular myocytes) generates a body surface potential captured in the electrogram (ECG). Malfunctions within
the clock hierarchy produce abnormal ECGs (Fig. 1, right).
Editorial Focus
C942
A hierarchical clock system initiates and executes the heart beat
Sinoatrial Node
Impulse
initiation
Electrocardiogram
Bmal1-/-
Control
mice
Atria
Normal:
Rhythmic
R
Abnormal impulse
generation:
Slow and
dysrhythmic
R
His-Purkinje
Ventricular myocytes
Q
S
Normal:
Short QRS
The Fractal that drives sinoatrial node cell
Phosphodiesterases
AC
Phosphatases
cAMP PKA
Ca2+-Calmodulin
CaMKII
Phosphorylation
+ Ca2+
Q
S
Abnormal:
Long QRS
function
Sarcoplasmic reticulum Ca2+ cycling
Sarcolemmal ion channels ensemble
Mitochondrial ATP production
Myofilament contractions
Nucleus gene expression
Beat-to-beat
short range
Long range
Fig. 1. Rhythmic initiation (electrical component) and execution (contractile component) of each heartbeat by a hierarchical clock system (brain-heart) that
synchronizes functions of cells within and among other tissues. Impulse is initiated in the sinoatrial node (SAN) and conducted to ventricular myocytes. Bottom:
SAN pacemaker cells generate rhythmic electrical impulses that emerge from the SAN. Right panels schematically illustrate that heart-specific disruption of
circadian clock (Bmal1-/-) results in abnormal rhythm and rate (ECG) and impulse conduction (QRS).
translation of proteins involved in the regulation of long- and
short-range cardiac rhythmicity.
How Do Na Channels Participate in Regulation of the Heart
Rate and Rhythm?
Cells within each component of the clock hierarchy (Fig. 1)
have Na⫹ channels. In mice, Nav1.5 is absent from the center but
present in the periphery of the SAN, whereas Nav1.1 (neuronal
isoform) is present throughout the SAN (9). Both Na⫹ channel isoforms are likely important for SAN function in mice: the
two isoforms are involved in impulse initiation, but only the
cardiac Nav1.5 isoform participates in propagation of the action
potential from the SAN to the surrounding atrial muscle. HCN4positive-Cx43-negative cells within atrioventricular (AV) node or
His bundle, and Purkinje fibers in mice have high expression
levels of Nav1.5 (14). Moreover, a late Na⫹ current via Na⫹
channels that operate in slow gating modes [as opposed to transient INa that generates the action potential (AP) upstroke] is found
in ventricular myocytes. In heart failure, transient INa is reduced,
but late INa increases, and is involved in arrhythmias, due to
effects to disperse AP repolarization, and create cell Ca2⫹ overload, with attendant increase in diastolic Ca2⫹ levels and in
likelihood for the occurrence of spontaneous Ca2⫹ release (see
review in Ref. 11).
Regulation of the Cardiac Impulse beyond the Na⫹ Channels
But Na⫹ channels are only one component of the functions of
chemical and electrical clocks within components of the clock
hierarchy that generates, conducts, and executes cardiac impulse.
Recent discoveries have led to the idea that cardiac impulse
initiation and conduction involves the coupling of chemical to
electrical clocks within cardiac pacemaker cells (3, 8, 17). Numerous molecular clock functions, present within cells of each
tissue component of the hierarchical system in mice (10), become
synchronized to create an intracellular clock system that delivers
the “payload” of that cell type in a rhythmic manner with a
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AV Node
Impulse
Conduction
Autonomic
modulation via
neurotransmitters
Editorial Focus
C943
photons and this fractal may be implicated in the rhythmic
diurnal regulation of the heartbeat.
Future Directions
In summary, the study by Schroder et al., in demonstrating that
Scn5a is regulated by a cardiomyocyte circadian clock, uncovers
what is likely to be “a tip of the iceberg” of complex processes
distributed among fractals that control the function within and
among different cardiac cell types on a broad time scale (milliseconds to hours to days and beyond). Future studies are required
to test the hypothesis that clock genes regulate ultradian fractallike clock regulation and synchronization of functions within cells
(as depicted for SANC in Fig. 1) of other tissues components of
the depicted hierarchy and that these same fractals link ultradian
rhythms to circadian rhythms.
GRANTS
This research was supported entirely by the Intermural Research Program of
the National Institutes of Health, National Institute on Aging.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
E.G.L., Y.Y., and V.A.M. drafted the manuscript; edited and revised the
manuscript; approved the final version of the manuscript.
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Editorial Focus
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