European Heart Journal (2006) 27, 2919–2920
doi:10.1093/eurheartj/ehl374
Hypertension begets hypertrophy begets atrial
fibrillation? Insights from yet another sheep model
Paulus Kirchhof1,2* and Ulrich Schotten2,3
1
Department of Cardiology and Angiology, University Hospital Münster and IZKF Münster, Münster, Germany;
2
German Atrial Fibrillation Competence NETwork (AFNET), Germany; and 3 Department of Physiology,
University of Maastricht, Maastricht, Germany
Online publish-ahead-of-print 15 November 2006
This editorial refers to ‘Atrial electrical and structural
abnormalities in an ovine model of chronic blood pressure
elevation after prenatal corticosteroid exposure: impli-
cations for development of atrial fibrillation’† by
P.M. Kistler et al., on page 3045
Atrial fibrillation (AF) affects approximately two million
patients in the USA and an equal number in Europe and
increases morbidity and mortality in affected patients and
population worldwide. Although acute conversion of AF to
sinus rhythm can be achieved in almost all patients, thera-
peutic options to maintain sinus rhythm (repeated cardio-
versions, anti-arrhythmic drugs, catheter ablation, or
surgical procedures) are often ineffective. Understanding
the different mechanisms that contribute to AF may guide
us towards a more effective ‘rhythm control’ therapy.
Arterial hypertension, found in 65–70% of AF patients1,2 but
only in 25–50% of the population,3 is the most common
co-morbidity found in AF registries in Germany and Europe.
Although this suggests a causal link between hypertension
and AF, the mechanisms by which hypertension predisposes
to AF are not well understood. Electrical, structural, and
ultrastructural changes usually concur in the atria before AF
develops. Some of the electrical changes that precipitate
AF, shortening of the atrial action potential and refractory
period and/or local conduction disturbances, have been
delineated in detail during the past decade. The underlying
pathophysiological concept of electrical remodelling
(AF-induced shortening of atrial refractoriness) stems from
studies in a goat model with pacing-induced AF (‘AF begets
AF’).4 In this issue of the European Heart Journal, Kistler
et al.5 report observations in a sheep model that provide
insights into potential mechanisms by which chronic
‘isolated’ arterial hypertension can beget AF.
Kistler et al. used maternal treatment with corticoster-
oids to induce post-natal, life-long arterial hypertension in
The opinions expressed in this article are not necessarily those of the
Editors of the European Heart Journal or of the European Society of
Cardiology.
* Corresponding author: Medizinische Klinik und Poliklinik C, Kardiologie
und Angiologie, Universitätsklinikum Münster, D-48129 Münster, Germany.
Tel: þ49 251 8345185; fax: þ49 251 8347864.
E-mail address: kirchhp@uni-muenster.de
{
doi:10.1093/eurheartj/ehl360
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Editorial
sheep. Although the cause of hypertension in men might
Downloaded from eurheartj.oxfordjournals.org by guest on September 21, 2010
differ from the mechanisms in this animal model, the
study delineates mechanisms that promote the initiation
and perpetuation of AF in the hypertensive heart. First of
all, the study provides experimental evidence that hyper-
tension creates a substrate for AF. Prenatal steroid treat-
ment not only caused life-long hypertension, but also
markedly prolonged AF episodes induced by aggressive
pacing (mean AF duration 84 vs. 0.5 s) in old sheep
(4.5 years or age). There was no evidence for a shortening
of atrial refractoriness, but the atrial structure was
altered, with cellular hypertrophy, patchy fibrosis,
increased collagen content, and myolysis. Altered atrial
structure and atrial fibrosis can form a ‘substrate’ for AF
and are the most likely explanation for conduction
slowing, conduction barriers, and increased inducibility of
AF in this model, comparable with the changes found in
failing dog hearts.6
Although it has long been known that hypertension pro-
vokes a hypertrophic response in the ventricular myocar-
dium, the paper by Kistler et al. extends this finding to
the atria and suggests that atrial hypertrophy, provoked in
response to chronically elevated blood pressure, may be
the pathophysiological link that connects arterial hyperten-
sion and AF.
The effect of elevated blood pressure on atrial conduction
described by Kistler et al. was even more pronounced than
conduction disturbances demonstrated by others in structu-
rally remodelled atria. In models of atrial dilatation or heart
failure,6,7 conduction was slowed exclusively at high rates or
during premature atrial stimulation. In hypertensive sheep,
conduction is already slow at low rates, more resembling
electrophysiological remodelling in dilated atria of patients
with heart failure.8 This difference might be related to
different mechanisms inducing structural remodelling or to
the long time during which the substrate could develop
(4.5 years).
The authors suggest that activation of the renin–
angiotensin system, one of the most powerful stimuli for
cardiac hypertrophy, could provoke the atrial hypertrophic
response in their model. The morphological and electro-
physiological changes in the atria of failing dog hearts
subjected to ventricular tachypacing6 are of striking resem-
blance to the changes induced by long-standing arterial
2920
hypertension in the present model: atrial hypertrophy,
increased atrial fibrosis, conduction slowing, and prolonged
duration of induced AF. Blockade of the renin–angiotensin
system can prevent structural remodelling associated with
AF in dogs with pacing-induced heart failure.6 In the LIFE
study, regression of cardiac hypertrophy—assessed as left
ventricular hypertrophy—was associated with prevention of
new-onset AF, irrespective of classical risk factors for AF or
treatment allocation.9 The sequence of events suggested by
the data of Kistler et al. and by these studies—hypertension
activates the renin–angiotensin system, induces (atrial)
hypertrophy, and thereby causes structural remodelling
of the atria—could explain why inhibition of the renin–
angiotensin system is so effective in the prevention of
AF.9,10 Further studies are warranted to assess the activity
of the renin–angiotensin system and the effects of its
pharmacological blockade in this model. In addition, the
effect of lowering blood pressure without interfering with
the renin–angiotensin system on the structural remodelling
process and the substrate for AF might be of interest.
As in all models, there are limitations. The authors did not
search for spontaneous AF. The role of atrial stretch as a
trigger for atrial or pulmonary vein automaticity has not
been explored. Furthermore, although pre-natal steroid
treatment is accepted as a model for hypertension,
increased blood pressure is a consequence of a foetal inter-
vention, causing altered steroid-regulated gene expression.
Cardiac hypertrophy could be a consequence of this
prenatal intervention rather than a response to hyperten-
sion. Last but not least, other signalling cascades than the
renin–angiotensin system can provoke atrial hypertrophy,
fibrosis, and cell death; these should be studied. The
paper by Kistler et al.5 establishes a link between hyperten-
sion and AF and thereby introduces atrial hypertrophy as a
potential new target for rhythm control treatment in
patients with AF.
Acknowledgement
This study was supported by the German Ministry of Education and
Research BMBF (AFNET, Gi020407).
Editorial
Conflict of interest: The authors have received research grants and
honoraria from pharmaceutical companies for studies related to AF.
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