Phosphodiesterase-4 activity: a critical modulator of atrial contractility and arrhythmogenesis.
A Critical Modulator of Atrial
Contractility and Arrhythmogenesis*
David R. Van Wagoner, PHD,†
Bruce D. Lindsay, MD‡
Atrial excitation-contraction coupling (ECC) and pace-
maker activity are both dependent on intracellular calcium
(Ca2?) cycling, and alterations in Ca2?cycling are strongly
implicated in the pathophysiology of atrial fibrillation (AF).
Depolarization of cardiac myocytes promotes Ca2?influx
via L-type calcium channels (LTCCs), which then releases
a larger quantity of Ca2?from intracellular stores. For
ECC, elevated Ca2?interacts with troponin C, promoting
cross bridge interaction and myocyte contraction. Relax-
ation during diastole requires intracellular Ca2?levels to
return to baseline levels, either via reuptake of Ca2?into the
sarcoplasmic reticulum or extrusion from the cell by the
sodium calcium exchanger. In pacemaking cells, Ca2?influx
via the LTCC underlies the upstroke of the action potential;
Ca2?(and sodium) influx via HCN (hyperpolarization-
activated cyclic nucleotide-gated) channels regulates the rate
of diastolic depolarization.
See page 2182
Given the critical role of Ca2?cycling in atrial contractile
and pacemaker functions, it is not surprising that these
processes are highly regulated. Sympathetic nerve activity
increases heart rate and cardiac output by increasing Ca2?
influx and cycling in both the sinoatrial (SA) node and in
the working atrial myocardium. Norepinephrine released
from cardiac nerve terminals activates beta-adrenergic re-
ceptors (beta-ARs) in the heart. Beta-AR activation in-
creases production of cyclic adenosine monophosphate
(cAMP). Parasympathetic (vagal) activity suppresses forma-
tion of cAMP, by inhibiting the activity of adenylate
cyclase. Elevated cAMP levels increase protein kinase A
(PKA) activity, promoting the phosphorylation of the
LTCC, ryanodine receptor, HCN channels, troponin I, and
phospholamban. Thus, during sympathetic stimulation,
Ca2?influx is enhanced, heart rate is increased, the Ca2?
transient is larger, contractile activity is increased, and
reuptake of Ca2?into the sarcoplasmic reticulum is en-
hanced. Enhanced Ca2?cycling comes at the cost of
increased demand for adenosine triphosphate, oxygen, and
When sympathetic activation subsides, intracellular phos-
phodiesterases (PDEs) degrade cAMP, reducing PKA ac-
tivity. Atrial PDEs are important modulators of heart rate,
cardiac contractility, and energy demand. Too little PDE
activity can lead to prolonged tachycardia, increased con-
tractile activity, and enhanced pacemaker activity—both in
the sinoatrial node and in secondary pacemakers (such as
those in the pulmonary vein region or around the mitral
valve). This can promote Ca2?overload, initiate myocyte
apoptosis, and act as a trigger for AF. Too much PDE
activity can diminish the ability of the heart to respond to
stress and reduce cardiac contractile activity. We and others
have shown that in persistent AF, perhaps as an adaptation
to rate-induced intracellular Ca2?overload, Ca2?influx
through the LTCC is reduced (1), leading to impaired
contractility, and increasing risk of thrombus formation and
stroke (2). PDEs thus have a significant impact on atrial
contractile and electrical activity, and can affect risk of AF
PDE isoforms vary in substrate specificity (degrading
cAMP, cyclic guanosine monophosphate, or both). They
have different kinetics and affinity for cyclic nucleotides.
The intracellular localization and regional distribution of
PDEs vary. PDE3 is the most abundant PDE expressed in
human atria. Previous pharmacological studies character-
ized, in detail, the impact of PDE3 inhibitors on the
adrenergic responses of human atrial myocyte contractility
and calcium currents (3–5). Although PDE3 is the most
abundant PDE in the human atrium, it is not the only
In this issue of the Journal, Molina et al. (6) carefully
document the presence, function, and significance of PDE4
(A, B, and D) isoforms in human atrial myocytes. Using a
combination of classical and state-of-the-art techniques, the
investigators synthesize a novel and coherent understanding
of the physiological significance of PDE4 in human atria.
The authors show that although PDE4 constitutes only
about 15% of total PDE activity, PDE4 isoforms have a very
significant impact on cAMP levels and on the Ca2?channel
response to beta-ARs agonists. They demonstrate that
PDE4 A, B, and D isoforms are expressed in human atrial
myocytes, and report that PDE4D is the most abundant. In
isolated human atrial myocytes, pharmacological inhibition
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the †Departments of Molecular Cardiology and Cardiovascular Medicine,
Cleveland Clinic, Cleveland, Ohio; and the ‡Department of Cardiovascular Medi-
cine, Cleveland Clinic, Cleveland, Ohio. This study was funded by the Atrial
Fibrillation Innovation Center, an Ohio Wright Center Initiative, the Fondation
Leducq European North American Atrial Fibrillation Research Alliance (07-
CVD03), National Institutes of Health grant R01-HL090620, and a research
contract from Gilead Sciences (unrelated to editorial focus). Dr. Van Wagoner has
received research grants from Gilead Sciences. Dr. Lindsay has reported that he has
no relationships relevant to the contents of this paper to disclose.
Journal of the American College of Cardiology
© 2012 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 59, No. 24, 2012
of PDE4 activity during exposure to beta-ARs was associ-
ated with a prolongation of the increase in cAMP levels.
PDE4 inhibition increased LTCC density and increased
the rate of spontaneous sarcoplasmic reticulum calcium
release events. Similarly, in intact human atrial trabeculae,
inhibition of PDE4 activity increased the contractile re-
sponse to beta-ARs and increased arrhythmic contractile
Interestingly, the investigators were able to assess PDE
activity in right atrial tissues from 18 patients in sinus
rhythm and 7 patients with permanent AF. Total PDE
activity was ?25% lower in patients with AF compared with
those in sinus rhythm (p ? 0.059). The difference was even
greater with respect to PDE4 activity, which was reduced by
48% in AF patients versus those in sinus rhythm (p ?
0.029). The investigators noted (not surprisingly) that the
AF patients were older than those in sinus rhythm. Regres-
sion analysis confirmed that PDE4 activity was negatively
associated with age. In an age-matched comparison, the
difference between patients with AF versus those in sinus
rhythm was smaller, but still approached statistical signifi-
cance (p ? 0.057). It thus seems likely that loss of PDE4
activity contributes to AF risk, and that the presence of AF
is associated with a further reduction in PDE4 activity.
Although a number of pro-arrhythmic pathways (sympa-
thetic tone, hypertension, fibrosis, and so on.) also increase
in prevalence with age, the results of Molina et al. (6) are
These studies suggest that, by minimizing Ca2?influx
and spontaneous release events, PDE4 decreases the fre-
quency of Ca2?release mediated ectopic events and protects
against arrhythmic activity. The studies in this report
focused on right atrial appendage tissue specimens. As
much of the current clinical focus on AF treatment centers
on isolation of ectopic activity originating in the pulmonary
vein region of the left atrium, it would be of interest in
future studies to evaluate the regional abundance and
distribution of PDE isoforms in the left and right atrial
bodies, appendages, SA and atrioventricular nodes, and in
the pulmonary vein region.
A primary concern for AF patients is the risk of cardio-
embolic stroke; AF increases risk of stroke 5- to 7-fold (7).
Molina et al. (6) note that PDE4D has been linked to stroke
risk in genome-wide association studies with stroke end-
points (8,9), but point out that these studies have not yet
considered the possibility that atrial PDE4D may underlie
this relationship. On the basis of the results presented, this
seems to be a logical and important hypothesis. In genome
wide association studies of AF cohorts (10,11), it will be
possible to assess the role of PDE4D as a candidate gene
associated with stroke risk. In such a study, if the number of
strokes reported is sufficient, it should be straightforward to
evaluate the hypothesis that atrial PDE4D activity is caus-
ally related with stroke as a result of AF.
AF is the most common arrhythmia, and currently
available antiarrhythmic treatments based on ion channel
blockade have limited efficacy. Considerable recent effort
has focused on the development of novel anticoagulants that
help to reduce stroke risk in AF. Although these agents are
welcomed and are likely to be exceptionally valuable, the
study of Molina et al. (6) suggests the intriguing hypothesis
that novel agents that selectively enhance PDE4D activity
might simultaneously prevent atrial contractile dysfunction,
limit atrial energy demands associated with Ca2?cycling,
help to prevent AF, and decrease stroke risk. Efforts to test
this hypothesis would represent a significant step toward
more effective management of AF.
Reprint requests and correspondence: Dr. David R. Van Wag-
oner, Cleveland Clinic, M/S NE-61, 9500 Euclid Avenue, Cleve-
land, Ohio 44195. E-mail: firstname.lastname@example.org.
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Key Words: atrial fibrillation y calcium channel y calcium cycling y
human atrial myocytes y phosphodiesterase activity.
2192Van Wagoner and Lindsay
JACC Vol. 59, No. 24, 2012
June 12, 2012:2191–2