Phosphodiesterase-4 activity: a critical modulator of atrial contractility and arrhythmogenesis.
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ABSTRACT: Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.Nature Genetics 02/2010; 42(3):240-4. · 35.21 Impact Factor
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ABSTRACT: The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.Circulation 03/2009; 119(4):606-18. · 15.20 Impact Factor
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ABSTRACT: beta(1)- and beta(2)-adrenoceptors coexist in rat heart but beta(2)-adrenoceptor-mediated inotropic effects are hardly detectable, possibly due to phosphodiesterase (PDE) activity. We investigated the influence of the PDE3 inhibitor cilostamide (300 nmol x L(-1)) and the PDE4 inhibitor rolipram (1 micromol x L(-1)) on the effects of (-)-catecholamines. Cardiostimulation evoked by (-)-noradrenaline (ICI118551 present) and (-)-adrenaline (CGP20712A present) through beta(1)- and beta(2)-adrenoceptors, respectively, was compared on sinoatrial beating rate, left atrial and ventricular contractile force in isolated tissues from Wistar rats. L-type Ca(2+)-current (I(Ca-L)) was assessed with whole-cell patch clamp. Rolipram caused sinoatrial tachycardia. Cilostamide and rolipram did not enhance chronotropic potencies of (-)-noradrenaline and (-)-adrenaline. Rolipram but not cilostamide potentiated atrial and ventricular inotropic effects of (-)-noradrenaline. Cilostamide potentiated the ventricular effects of (-)-adrenaline but not of (-)-noradrenaline. Concurrent cilostamide + rolipram uncovered left atrial effects of (-)-adrenaline. Both rolipram and cilostamide augmented the (-)-noradrenaline (1 micromol x L(-1)) evoked increase in I(Ca-L). (-)-Adrenaline (10 micromol x L(-1)) increased I(Ca-L) only in the presence of cilostamide but not rolipram. PDE4 blunts the beta(1)-adrenoceptor-mediated inotropic effects. PDE4 reduces basal sinoatrial rate in a compartment distinct from compartments controlled by beta(1)- and beta(2)-adrenoceptors. PDE3 and PDE4 jointly prevent left atrial beta(2)-adrenoceptor-mediated inotropy. Both PDE3 and PDE4 reduce I(Ca-L) responses through beta(1)-adrenoceptors but the PDE3 component is unrelated to inotropy. PDE3 blunts both ventricular inotropic and I(Ca-L) responses through beta(2)-adrenoceptors.British Journal of Pharmacology 02/2009; 156(1):62-83. · 5.07 Impact Factor
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: email@example.com.
1. Van Wagoner DR, Pond AL, Lamorgese M, Rossie SS, McCarthy
PM, Nerbonne JM. L-type Ca2?currents and human atrial fibrilla-
tion. Circ Res 1999;85:428–36.
2. Benjamin EJ, Chen PS, Bild DE, et al. Prevention of atrial fibrillation:
report from a national heart, lung, and blood institute workshop.
3. Li Q, Himmel HM, Ravens U. Effects of the new phosphodiesterase-
III inhibitor R80122 on contractility and calcium current in human
cardiac tissue. J Cardiovasc Pharmacol 1994;24:133–43.
4. Christ T, Engel A, Ravens U, Kaumann AJ. Cilostamide potentiates
more the positive inotropic effects of (-)-adrenaline through beta(2)-
adrenoceptors than the effects of (-)-noradrenaline through beta
(1)-adrenoceptors in human atrial myocardium. Naunyn Schmiede-
bergs Arch Pharmacol 2006;374:249–53.
5. Christ T, Galindo-Tovar A, Thoms M, Ravens U, Kaumann AJ.
Inotropy and L-type Ca2? current, activated by beta1- and beta2-
adrenoceptors, are differently controlled by phosphodiesterases 3 and 4
in rat heart. Br J Pharmacol 2009;156:62–83.
6. Molina CE, Leroy J, Richter W, et al. Cyclic adenosine monophos-
phate phosphodiesterase type 4 protects against atrial arrhythmias.
J Am Coll Cardiol 2012;59:2182–90.
7. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an indepen-
dent risk factor for stroke: the Framingham Study. Stroke 1991;22:
8. Bevan S, Porteous L, Sitzer M, Markus HS. Phosphodiesterase 4D
gene, ischemic stroke, and asymptomatic carotid atherosclerosis.
9. Milton AG, Aykanat VM, Hamilton-Bruce MA, Nezic M, Jannes J,
Koblar SA. Association of the phosphodiesterase 4D (PDE4D) gene
and cardioembolic stroke in an Australian cohort. Int J Stroke
10. Ellinor PT, Lunetta KL, Glazer NL, et al. Common variants in
KCNN3 are associated with lone atrial fibrillation. Nat Genet 2010;
11. Pfeufer A, van NC, Marciante KD, et al. Genome-wide association
study of PR interval. Nat Genet 2010;42:153–9.
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