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Journal of the American College of Cardiology Vol. 56, No. 17, 2010
© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2010.05.042
EDITORIAL COMMENT

he Tell-Tale Heart
Now, Optically Mapped)*

iguel Valderrábano MD,
mish S. Dave MD, PHD

ouston, Texas

n Edgar Allan Poe’s short story (1) published in 1843, a
ameless narrator murders an old man, dismembers the
ody, and then hides it under the floorboards. When the
olice come to investigate, the murderer becomes quickly
ormented by what he perceives is the sound of the dead
an’s heartbeat and compels the officers to tear up the

oorboards. As with the narrator in Poe’s classic work of
ction, countless researchers over the last century have been
ompelled to seek out the source of the heartbeat.

See page 1386

The sinoatrial node (SAN) has similarly obsessed anato-
ists, physiologists, and cardiologists for more than 100

ears since its original description by Keith and Flack in
907 (2). The fascination spans the spectrum from the
olecular origins of pacemaker automaticity to the ana-

omic and physiologic mechanisms of macroscopic propa-
ation of the sinus node impulse to neighboring atrial tissue.
t all levels, fascination has been accompanied by contro-

ersy. Even 1 of the discoverers of the SAN is controversial,
ir Arthur Keith being allegedly involved (3) in the scien-
ific scandal involving the fabrication of “piltdown man,” an
volutionary missing link. Recently, Circulation Research
ublished a series of articles reviewing and revitalizing
ontroversies around the SAN (4 – 8). The molecular mech-
nisms of pacemaker activity generation have been disputed
etween several proposed mechanisms, including various
nward membrane currents (If, T- and L-type Ca

2� cur-
ents, the “membrane voltage clocks”) as well as intracellular
a2� cycling (the “calcium clocks” (7,9,10), involving re-

ease from the sarcoplasmic reticulum and possibly store-
perated Ca2� channels [11]). Details of the generation of
he pacemaker activity can be found elsewhere (7).

Editorials published in the Journal of the American College of Cardiology reflect the
iews of the authors and do not necessarily represent the views of JACC or the
merican College of Cardiology.
From the Division of Cardiac Electrophysiology, Department of Cardiology,
c
ethodist Hospital, Houston, Texas. Both authors have reported that they have no

elationships to disclose.
Just as interesting, however, are the mechanisms of
mpulse conduction from the SAN to the atria at the

acroscopic level. Successful propagation from the central
acemaker cell (or group of cells) to atrial tissue is a
remendous physiological challenge. Normal propagation in
ardiac tissue entails a delicate balance between depolarized
ells (source) and the resting tissue ahead (sink) (12).
xcited cells serve as a source of electric charge for depo-

arizing neighboring cells (sink). The relationship between
ource and sink defines the safety factor of propagation. A
arge volume of excited tissue (source) will easily propagate
nto a small volume of quiescent tissue (sink). Alternatively,
f the sink is too large, propagation fails due to a source–sink

ismatch. How does the SAN manage to take depolariza-
ion from a small group of cells into the entire atrial tissue?
ellular coupling holds the key to this challenge. In con-
uction failure due to source–sink mismatch, propagation
ails because cells close to the wave front fail to depolarize as
he neighboring, well-coupled unexcited tissue downstream
olds their membrane potential polarized. It is known that
ropagation from a small group of cells (source) into a large
roup of well-coupled cells (sink) has a low safety factor and
s likely to fail. In this scenario, decreasing cellular cou-
ling— e.g., via decreasing gap junction conductance— can
aradoxically enhance propagation success, despite slowing
onduction velocity (13). It is intuitive that a similar
echanism must play a role in propagating SAN conduc-

ion. The slow conduction within the SAN supports un-
oupling as a mechanism of slow-but-safe propagation.
ow to successfully conduct from SAN to sites of initial

trial activation remains challenging to explain.
Mapping studies (14,15) have shown that initial atrial

ctivation sites can vary widely during sinus rhythm. In their
914 study, Meek and Eyster (15) used multiple string
alvanometers and, by identifying locations with initial
lectrical negativity under conditions of vagal stimulation or
ocalized cooling, observed that initial atrial activation sites
an vary. In 1978, Boineau et al. (16) observed a trifocal
rigin of the atrial waveform in the dog using multiple
ipolar atrial electrode recordings. The subsequent
oineau-Schuessler SAN model proposed the existence of
iscrete conduction pathways connecting the SAN with
trial tissue to explain beat-to-beat divergent activation sites
16 –18).

In this issue of the Journal, Fedorov et al. (19) add to the
uthors’ extensive contribution over many years to the study
f the SAN. In particular, the development of the technique
f optical mapping has provided a modality by which to
tudy the relationship between SAN anatomy and physiol-
gy to begin to explain SAN function. Applying this
echnique, they recently found evidence for discrete exit
athways connecting the SAN and atria in the dog (20).
hey were able to directly map the conduction inside the

anine SAN and atrium, and identified 2 or more discrete

onduction pathways directed superiorly or inferiorly from



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1396 Valderrábano and Dave JACC Vol. 56, No. 17, 2010
The Tell-Tale Heart October 19, 2010:1395– 6
he SAN. Interestingly, they measured slowing of conduc-
ion velocity in these pathways down to 2 cm/s, and
ttributed this to source–sink mismatch. They concluded
hat the etiology of multifocal atrial activation is due to the
ossibility of atrial excitation from any of multiple discrete
AN exit pathways. In the current report, they have
xtended these findings to the human, for the first time
pplying optical mapping techniques to obtain voltage
ecordings of the coronary perfused intact human SAN and
earby atria during normal sinus rhythm. They confirm the
uman SAN is electrically insulated from nearby atrial
yocardium with the exception of several discrete exit

athways, noting a similar slowing of conduction within
hese pathways as in the canine study. From the source–sink
ismatch point of view, this insulation makes sense and

eems necessary: if the atrial tissue were well coupled to the
acemaker cells, propagation within the SAN would fail due
o excessive current sink.

Controversies remain in the interpretation of the optical
ction potential signals (which are a superposition of signals
rom overlapping atrial myocardium and SAN layers) as
ell as in the role of calcium dynamics in pacemaker activity

5). Notwithstanding such, understanding the mechanism
hat overcomes the source–sink mismatch is likely to have
mportant clinical implications. The authors suggest that
ecreased conduction velocity is a result of the mismatch;
nother explanation may be that cell– cell coupling is re-
uced in these exit pathways so as to increase the safety
actor for propagation, i.e., to overcome the source–sink
ismatch. These questions and more remain; however, the

urrent report continues a fruitful tradition of comparative
hysiology research going back over 100 years, and thanks
o this work, we are no doubt closer to solving the
ontroversies than ever before.

eprint requests and correspondence: Dr. Miguel Valderrábano,
ethodist Hospital, 6560 Fannin Street, Suite 1144, Houston,

exas 77030. E-mail: MValderrabano@tmhs.org.

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3. Tobias PV. Piltdown: an appraisal of the case against Sir Arthur Keith.
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4. O’Rourke B. Be still, my beating heart: never! Circ Res 2010;106:
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ey Words: bradycardia y exit pathway y optical mapping y sinus node.

mailto:MValderrabano@tmhs.org