Download Looking Beyond the Ablation Shore, Treating Atrial

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 65, NO. 9, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2014.12.025
EDITORIAL COMMENT
Looking Beyond the Ablation Shore,
Treating Atrial Fibrillation From Afar
Integrating Anatomic, Physiologic, Neurologic, and
Cardiovascular Principles Into Novel Therapies*
Suraj Kapa, MD,y David J. Callans, MDz
One doesn’t discover new lands without consenting
to lose sight, for a very long time, of the shore.
I
—André Gide, Les faux-monnayeurs (1)
t is certainly difficult to be a patient with atrial
fibrillation (AF) or an electrophysiologist caring
for this patient. We live with the frustration
related to the seemingly capricious nature of ablation
success for AF, trapped in the hope that constructing
a slightly altered lesion set, using a newer catheter,
or processing signals differently will allow for a major
scientific breakthrough. In fact, the last 20 years of
research in AF have been characterized by a preponderance of work on potentials and pulmonary veins.
More recently, however, we have come to again
appreciate the role of the autonomic nervous system
in cardiac arrhythmias—a role that has been well
recognized since the 1970s, starting with pioneering
work by Kapa et al. (2) and Coumel et al. (3). Though
initially considered a sympathetically mediated phenomenon, further study led to the understanding
that parasympathetic effects on atrial dispersion as
well as sympathetic effects may be involved in AF
pathogenesis (4–6). In fact, the higher incidence of
AF during sleep has been felt to be due to a profound
parasympathetic dominance and, in turn, perhaps an
increased sympathetic drive converting to a vagal
predominance and AF onset (7,8).
Decades of large animal work by the University of
Oklahoma group has demonstrated a relationship
between the autonomic nervous system and phenomena related to AF initiation and maintenance
(9–11). This relationship is borne out by simple anatomy: the highest density of nerve endings in the
human atria occur at the pulmonary vein/atrial
interface; the usual response of ablation at the pulmonary veins is bradycardia rather than tachycardia;
and ganglionated plexi that relay vagal and sympathetic efferents to myocardial cells are principally
distributed around the heart’s posterior surface
including in proximity to the pulmonary veins. This
has led to the assumption that ablation of such
ganglia and nerve endings may facilitate AF treatment, though this has not been demonstrated
consistently in patient studies, potentially due to
the difficulty of identifying ganglia, the limitations
of existing ablation technology, and the potential
for reinnervation or nerve regrowth at the site of
successful ablation (12–14).
Alternative therapies were then proposed to not
just destroy autonomic inputs but to modulate their
activity through stimulation or ablation of extracardiac structures. For example, low-level vagus
nerve stimulation (LLVNS) makes AF more difficult to
*Editorials published in the Journal of the American College of Cardiology
induce by lengthening AF cycle length and prevent-
reflect the views of the authors and do not necessarily represent the
ing electrical (shortening of the atrial refractory
views of JACC or the American College of Cardiology.
period and dispersion of refractoriness) and auto-
From the ySection of Cardiac Electrophysiology, Division of Cardiology,
nomic remodeling (through burst firing of cardiac
Mayo Clinic College of Medicine, Rochester, Minnesota; and the zSection
ganglionated plexi) caused by rapid atrial pacing
of Cardiac Electrophysiology, Division of Cardiology, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Both
(15,16). These observations form the basis of the
authors have reported that they have no relationships relevant to the
“autonomic hypothesis”: hyperactivity of the cardiac
contents of this paper to disclose.
autonomic nervous system causes/maintains AF; in
Kapa and Callans
JACC VOL. 65, NO. 9, 2015
MARCH 10, 2015:876–8
Novel Therapies for Atrial Fibrillation
turn, modulating the autonomic nervous system may
auricular portion of the vagus nerve on cardiac
effectively treat AF. Supportive evidence comes from
contractility
animal studies as well as from human studies of spi-
described since the 1970s, where features such as
nal cord stimulation, renal denervation, and vagal
hypotension, increased ventricular ectopy, and even
stimulation (2,17,18).
right bundle branch block were associated with
and
electrical
function
has
been
manipulation and sectioning of the upper vagal
SEE PAGE 867
rootlets in patients (22). Thus, we must consider the
The study by Stavrakis et al. (19) in this issue of
subtleties of this novel therapy because a simple
the Journal furthers this understanding via a novel,
paradigm of stimulation on/off or high energy/low
elegant approach that allows for a noninvasive, non-
energy may not offer a comprehensive enough un-
ablative, nonpharmacological therapy for AF. Study-
derstanding of its correct application. Therefore,
ing low-level transcutaneous electrical stimulation of
clinical studies of LLVNS must continue to be paired
the auricular branch of the vagus nerve at the level of
with physiological studies to avoid getting caught in
the tragus, they demonstrated that AF inducible by
the trap of advancing a therapy without first ensuring
rapid atrial pacing could be suppressed. Furthermore,
the structural integrity of its foundation.
such stimulation decreased levels of inflammatory
We hope that Stavrakis et al. (19) are correct and
cytokines in patients with paroxysmal AF, whereas
these lines of investigation will eventually lead to a
having minimal effects on sinus rate, atrioventricular
successful nonpharmacological, nonablative therapy
nodal properties, or blood pressure. These patients
for AF. More importantly, this study aims at under-
were studied under general anesthesia, so one must
standing the fundamental nature of AF and its patho-
wonder whether the “type” of AF reflected by
physiology. Many have argued that electrophysiology,
inducibility under general anesthesia necessarily re-
once a mostly intellectual pursuit firmly grounded
flects what is seen clinically; inducibility or lack
in our understanding of physiology, has lost its way.
thereof at the end of traditional ablation does not
By rediscovering our past to help innovate our future,
correlate with risk of clinical recurrence (20). Whether
we may be able to again harness the elegance of
LLVNS is effective for patients with discrete subtypes
the neural-cardiac interface to better manage our
of AF remains to be determined.
patients—more safely, effectively, and thoughtfully.
Much work remains, as Stavrakis et al. (19)
Ultimately, the effectiveness of interventions on the
mentioned. First, analysis of ambulatory patients is
basis of this knowledge remains to be determined.
necessary. This new study of LLVNS was done using
What is clear, however, is that there may be value to
general anesthesia, meaning the comfort factor for
electrophysiologists sometimes losing “sight of the
patients must be considered. Furthermore, it will be
shore” of ablation therapy to discover new and
critical to determine the level of stimulation required
potentially more effective options for patient care.
to achieve the desired suppressive effect. In other
mammalian hearts, there is a parabolic effect on the
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
cardiac response, with low-level stimulation affecting
David J. Callans, Section of Cardiac Electrophysi-
features of cardiac contractility differently than
ology, Division of Cardiology, Perelman School of
higher outputs would (21). Whether this applies to
Medicine, University of Pennsylvania, 3400 Spruce
the heart’s electrical properties is less clear. In turn,
Street, Philadelphia, Pennsylvania 19104. E-mail:
the relationship of injury to, or stimulation of, the
[email protected].
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KEY WORDS atrial fibrillation, autonomic
nervous system, catheter ablation,
electrophysiology