ESC Congress FA eBook 2016 - 26

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October 2016

Figure 2. Atorvastatin Improves AF-Free Survival Compared
With Placebo
Atrial Fibrillation-Free Survival, %

Arrhythmogenic remodeling is central to understanding
AF. Remodeling might result from underlying cardiac conditions, systemic processes and conditions such as aging,
or potentially AF itself. Intracellular Ca2+ handling abnormalities and changes in microRNAs may provide important
insights into these adverse remodeling processes. Similarly,
it is hoped that biomarkers, and enhanced and noninvasive
monitoring/mapping will help quantify and characterize
the remodeling process [Nattel S et al. J Am Coll Cardiol.
2014].
A variety of modifiable factors affect the burden of AF.
Hypertension is associated with both an increased risk
of AF as well as early and progressive changes in atrial
remodeling [Lau DH et al. Heart Rhythm. 2010]. Among
obese men with an intermediate or poor level of physical
activity the risk of AF is increased 129%, and 156%, respectively [Huxley RR et al. Circ Arrhythm Electrophysiol. 2014];
however, weight reduction with intensive risk factor management significantly reduces AF symptoms and benefits
cardiac remodeling [Abed HS et al. JAMA. 2013].
In the LEGACY Study, long-term sustained weight loss
was associated with significant reduction of AF burden and
maintenance of SR. Arrhythmia-free survival with and without rhythm control strategies (ablation and antiarrhythmic
drugs) was significantly (P < .001) greater in patients with a
weight loss ≥ 10% compared with a weight loss of 3% to 9%,
a weight loss of < 3%, or weight gain [Pathak RK et al. J Am
Coll Cardiol. 2015].
Upstream therapy refers to the use of non-antiarrhythmic drugs that modify the atrial substrate or target specific mechanisms of AF to prevent the occurrence of the
arrhythmia. Giuseppe Boriani, MD, University of Modena
and Reggio Emilia, Modena, Italy, discussed the use of this
treatment approach in AF patients.
Upstream therapies to treat underlying disease in patient
with AF (eg, hypertension, heart failure [HF], inflammation) include angiotensin converting enzyme inhibitors,
angiotensin II-receptor blockers (ARBs), aldosterone
antagonists, statins, corticosteroids, n-3 polyunsaturated
fatty acids, ß-blockers, and possibly corticosteroids. The
key targets of upstream therapy are structural changes in
the atria, such as fibrosis, hypertrophy, inflammation, and
oxidative stress [Savelieva I et al. Europace. 2011].
The renin-angiotensin-aldosterone system plays a role
as a mediator of atrial remodeling in AF; consequently,
ARBs are suggested to potentially prevent LA dilatation,
atrial fibrosis, dysfunction, and conduction velocity slowing
[Aksnes TA et al. J Hypertens. 2007]. The ARB candesartan
can reduce AF duration by suppressing interstitial fibrosis
development [Kumagai K et al. J Am Coll Cardiol. 2003];
irbesartan reduces the risk of AF recurrence in patients
with persistent AF [Madrid AH et al. Circulation. 2002].
Results for statin therapy and modification of AF risk are
mixed. The statin atorvastatin may be effective treatment
for reducing the incidence of postoperative AF after elective
cardiac surgery when given preoperatively (Figure 2) [Patti
G et al. Circulation. 2006]. However, rosuvastatin appears

100

Atorvastin

Placebo

80
60
40

P = .003

20
0

Postoperative Days
Reprinted from Patti G et al. Randomized Trial of Atorvastatin for Reduction of Postoperative
Atrial Fibrillation in Patients Undergoing Cardiac Surgery. Circulation 2006;114(14):14451461. By permission of Wolters Kluwer. Copyright © 2006, American Heart Association, Inc.

ineffective and may cause acute kidney injury [Zheng Z et
al. N Engl J Med. 2016].
That AF begets AF is a commonly stated hypothesis used
to explain the progression its progressive natural history.
Gerhard Hindricks, MD, University of Leipzig Heart Center,
Leipzig, Germany, argued that this explanation may not be
applicable in humans and that it is likely other factors such
as progressive fibrosis that results in the progression of AF.
One study in patients with SR, lone AF, and AF with
underlying mitral valve disease and SR established an association with fibrosis, especially collagen I, but not collagen
III. No difference in major extracellular matrix proteins
between paroxysmal and chronic AF was noted [Boldt A
et al. Heart. 2004]. In another study, the fibrosis extent and
fatty infiltration were higher in patients with a history of AF
and correlated with lymphomononuclear infiltration. No
correlation was observed between age and fibrosis at any
of the locations examined, thus age is unlikely to be the
sole cause of advanced fibrosis underlying AF [Platonov PG
et al. J Am Coll Cardiol. 2011]. The degree of LA structural
remodeling as detected using delayed-enhanced magnetic
resonance imaging is independent of AF type and associated comorbidities [Mahnkopf C et al. Heart Rhythm. 2010].
There is no evidence of reverse atrial electroanatomic
remodeling after catheter ablation. Patients with lone AF
demonstrate evidence of an abnormal atrial substrate
(lower bipolar voltage, slowed conduction, more prevalent
complex signals, and prolonged effective refractory periods). These conditions did not appear to reverse even after
successful catheter ablation [Teh AW et al. Heart Rhythm.
2012].
Although human electrophysiology studies show remodeling in the early stages of AF, this remodeling may be
irreversible. Moreover, it seems possible that there is substrate progression despite successful ablation; suggesting
that early intervention is important.

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