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Heart Failure and Atrial Fibrillation:
Understanding the Pathophysiology as a Determinant of Treatment Strategy
Ronald Berger, MD, PhD
Johns Hopkins University
Baltimore, MD
Good morning. Thanks very much, and I want to thank Jag and the organizing
committee for inviting me, and for asking me to give this talk. Actually Jag asked me to
make it very futuristic, lots of molecules and space-age stuff, and well, I’ll do my best.
So, this is a rough outline of what I intend to go through. Basically, I’m trying to make this
an overview of some concepts that I think will lead into the discussions that we’re going
to have the debate that will be coming. Hopefully, I won’t step on too many of the points
of the speakers that are following me will undoubtedly want to make.
I’ll talk a little bit about the epidemiology and physiology of atrial fibrillation in heart
failure, talk about some of the novel therapies, some of the existing and novel therapies
for atrial fibrillation in that setting. And then, get into some of the therapies that I think are
relevant particularly to this conference on ablation and CRT, and then some devices
used at the end.
And, this is a slide that really brings coals to Newcastle talking about the different heart
failure trials that have gone on, and the prevalence of atrial fibrillation in the trials. And,
not surprisingly, those trials in which the heart failure was more severe had a higher
incidence of atrial fibrillation.
So, these conditions clearly co-exist, and the mechanisms of how one leads to the other
is a lot like the chicken and egg discussion. You can start anywhere in the cycle, but with
atrial fibrillation you have a loss of AV synchrony as well as a rapid ventricular response
and variability in our intervals.
That along with the toxicity and side effects and some of the drugs used to treat it can
lead to and exacerbate heart failure. Heart failure leads to a variety of processes
including volume pressure, overload fibrosis, which I’ll talk a little bit more about, and
then altered atrial electrical properties, all of which promotes atrial fibrillation and the
cycle continues.
And, to put a little more detail on it, this is a figure that I kind of like from a very recent
review of the subject which really goes over much of the same processes I just alluded
to, but pointing out some targets, potential targets for therapy, leading into the fibrosis as
somewhat of a central pathway, at least in this view of the world the renin angiotensin
aldosterone system contributes, and of course leads to targets that are traditionally used
to interrupt the process to ameliorate the process.
The fibrosis itself leads in through a variety of pathways that can alter conduction and
electrical properties of the atrium. And so, I’m going to talk a little bit about some of
those targets of therapy.
To go over the first, I think one of the most traditionally recognized targets, is block of the
renin angiotensin system with ACE inhibitors and ARBs. And, this is just a slide
reviewing a number of trials, heart failure, hypertension, arrhythmia trials in which the
risk of developing atrial fibrillation was reduced with ACE inhibitors and ARBs.
So, this is a well-established target in the process that improves both heart failure and
the arrhythmias that come from it, again through a variety of mechanisms interrupting
that vicious cycle that we talked about.
But, there are other targets in the process, as well, alluded to in those prior slides that
include the structural remodeling and fibrosis GAP junction, therapeutic targets,
especially those specific to atrial conduction and some atrial selective ion channel
targets as well, and I’ll talk a little bit about those.
Of course, there’s the old agents, even dronedarone is now being viewed as an old
agent in this paradigm of where can we attack our therapies, particularly atrial fibrillation
in this setting of heart failure where a lot of the therapies we would consider can be
proarrhythmic or detrimental in the setting of heart failure.
One of the points that I think is worth making is that atrial tissue electrically, to begin
with, is different from ventricular tissue, ion channel currents are somewhat different.
The action potential is shorter than what we see in ventricular tissue. There are a couple
of currents that are worth pointing out.
There’s an ultra-rapid outward potassium current as well as IKCH that are substantially
greater, different, or existing in atrial tissue not found in ventricular tissue. And then, in
the remodeled atrial tissue, with heart failure, or in the setting of atrial fibrillation, some of
the currents become further increased. The ultra-rapid K current, and then a
constitutively active IKCH, and this further abbreviates the action potential in atrial
fibrillation in atrial fibrillation and promotes the development of atrial fibrillation.
And so, there are atrially selective targets. You can see a variety of drugs, most of which
I never heard of before, vernakalant, being perhaps the only one I had. But, these
approach targets in atrial tissue that are different from those in ventricular tissue, again
the ultra-rapid K-current and a sodium, an atrial specific form of the K-current that
provide the opportunity for drugs that can alter the electrical properties of the atrium
without exacerbating ventricular electrical properties without being proarrhythmic,
particularly important features in the setting of heart failure.
And so, I’m not even going to talk about the traditional antiarrhythmic drugs that we have
used in atrial fibrillation, but rather point out that these newer agents are selective for ion
channels in atrium tissue. Some of these have been abandoned. For whatever reason,
the drug companies have decided that they will never make it to the light of day.
I think the one that’s particularly interesting is ranolazine. I’m going to stop and spend
just a moment talking about it. This is a drug that is an antianginal, but actually has very
interesting atrial selective ion channel effects, and is getting a lot of attention, I think, in
the EP community now.
And, just to make this point, ranolazine has an effect of sodium current in the atria as
well as selective outward current blockade that has the effect of extending the action
potential and the refractory period in a dose-related way in atrial tissue, but does not
have that effect in the ventricles.
So, as an example of a drug that is potentially antiarrhythmic in the atria without being
proarrhythmic, and just this week in JACC, the Antzelevitch Group, which is where this
slide comes from, have an article on synergy, synergistically using ranolazine and
dronedarone together as an even more potent antiarrhythmic combination for atrial
fibrillation. I think this is an area of drug therapy that is quite active now, not even talking
about the future.
And then, I just wanted to make the point, in an effort to be futuristic, as Jag was looking
for, that gene therapy is down the road, and may or may not ever make it as effective
therapy for atrial fibrillation. But, there have been some targets, most of these have
been––this is a review article from Kevin Donahue’s group at Metro Health of Case––
but, most of this work has been focused on altering AV nodal properties to slow down
the ventricular response in atrial fibrillation. But, some of the work has focused on
altering the electrical properties of atrial tissue itself in order to act as an antiarrhythmic
therapy.
Well, let me move on from the molecules and talk about something I know a little bit
more about, which is catheter ablation for atrial fibrillation, and talk about pulmonary vein
isolation.
And, I want to go over a couple of studies of clinical trials that I think are relevant to this
subject of pulmonary vein isolation for atrial fibrillation in this setting of heart failure or
impaired ventricular function. I think this is an area that I’m expected to comment on in
the Presidential Debate that follows. So, I’m taking the opportunity to cheat a little bit and
so you some slides now.
In any case, this is a trial that’s already fairly old published in 2004, from the Cleveland
Clinic group. And, this looked at almost 400 patients undergoing pulmonary vein
isolation. And, these were consecutive patients. And, about a quarter of them had
ejection fractions under 40%. And so, the group compared outcomes in those patients
with the remainder that had normal ventricular function, or at least ejection fraction
greater than 40%. And, what they found was first looking at AF-free survival that it was
better, statistically so in those with normal function versus those with impaired.
Now, you look at this graph and you say, this can’t be truth, it has to be something
fictitious here. No survival curve, I think in the intervening time since then, we know that
with a pulmonary vein isolation, it’s not possible for survival curve, for AF-free survival to
just flatten out like that.
In fact, you look at these curves and you say, have they simply made their blanking
period 60 days instead of 30, they would have had nearly 100% AF-free survival in
everybody. So, you know that something is a little bit fishy here. But, nonetheless it
makes the point that you can have a beneficial effect even in patients with heart failure.
Now, they didn’t find a statistically significant change in ejection fraction among those
who had EFs less than 40, well, it included those with EFs above 40% as well. But, I
wanted to go on and talk about a couple of other studies.
This is, I believe, from the Bordeaux [phonetic] group, they looked at 58 patients with
atrial fibrillation with heart failure, and in their case, ejection fraction under 45% and
compared it with 58 aged match controls with normal ventricular function.
And, first of all, looking at the AF-free survival at a year, it was similar, 78%. A little bit
lower in the heart failure patients compared to the controls, but, what was interesting
was if you looked at the patients who had the reduced ejection fraction, they found that
the LV function improved during the follow-up period quite substantially.
I mean, almost unbelievably so, with the average ejection fraction getting fully
normalized. And, furthermore, they found that those effects were there in the patients
regardless of whether they had some other structural heart disease or not, and
regardless of whether there was adequate rate control or not in the patients prior to
ablation.
So, rather impressive results showing that one can make patients with a combination of
atrial fibrillation and heart failure really remarkably better by pursuing pulmonary vein
isolation.
And then, the third trial that I want to discuss is a more recent trial published in 2008, a
multicenter trial called the PABA-CHF trial that compared two strategies in patients with
a reduced ejection fraction New York Heart Association class II or III and atrial
fibrillation, which was to compare pulmonary vein isolation versus AV node ablation plus
CRT, plus CRT pacemaker.
And, this wasn’t specifically persistent or chronic atrial fibrillation. In fact, half had
persistent and half had paroxysmal atrial fibrillation. And, this wasn’t in patients who had
native dyssynchrony, in general. The average QRS width was 90 ms in these patients.
So, the indication for the CRT was in those who had received AV node ablation, that
they were then going to be paced 100% of the time, and they had pre-existing reduced
ejection fraction, so that created the indication for CRT.
In any case, when you look at the results, in those who had the pulmonary vein isolation,
they achieved a nearly 80% freedom from atrial fibrillation with pulmonary vein isolation.
And then, when you look at a couple of their endpoints, so first looking at the Minnesota
living with heart failure questionnaire, at baseline the two groups were the same, but at
follow-up, only those who’d received the pulmonary vein isolation had improvement in
symptoms.
And, looking at a couple of the other endpoints, they found that those who’d been
randomized to pulmonary vein isolation enjoyed an improvement in ejection fraction,
whereas those who had AV node ablation and by the pacing did not.
And, similarly the six-minute walk results showed that those who had pulmonary vein
isolation enjoyed substantial improvement in distance achieved compared to those who
had been randomized to the strategy of AV node ablation plus BiV pacing.
And so, as a lead into CRT, therefore, I think it was useful to look at this retrospective
analysis from the CARE-HF study, asking the questions, does atrial fibrillation worsen
heart failure outcomes, and does CRT prevent atrial fibrillation.
So, just to review the CARE-HF study, 813 patients with New York Heart Association
class III or IV heart failure, ejection fraction of 35% or less, and QRS greater than 150
ms or narrower plus ECHO dyssynchrony without discussing whether or not these are
reasonable entry criteria. This is what it was.
But, they had to have not had persistent atrial fibrillation or atrial arrhythmias to get into
this study. And, of course they were randomized between CRT and no CRT. Now, a
number of patients did develop atrial fibrillation along the way during follow-up, and
that’s what this retrospective analysis looked at.
And, among those who developed new onset atrial fibrillation during follow-up, there was
an increase in all-cause mortality, compared to those who did not develop atrial
fibrillation. And, that was true for those randomized to medical therapy, and true for
those randomized to CRT.
In both groups, those who did or those who didn’t develop atrial fibrillation, there was
improved outcome with CRT, meaning reduced mortality. But, the atrial fibrillation
certainly led to worse outcomes than those without atrial fibrillation.
On the other hand, if you looked at freedom from AF in survivors comparing the CRT
group to the medical therapy group, there was no difference in the incidence of atrial
fibrillation, leading to these conclusions that atrial fibrillation worsens the outcome in
heart failure patients, but CRT does not prevent or cause atrial fibrillation.
And then, talking about CRT in atrial fibrillation versus sinus rhythm, this is a very nice
meta-analysis that Jag and Angelo authored, co-authored looking at five studies,
including Christophe’s where patients were compared, the efficacy of CRT in those with
sinus rhythm compared to those with chronic atrial fibrillation. This is as close as I’m
going to come to stepping on what’s going to be discussed in the debate. So, I don’t
want to talk too much about it, since I imagine you’ll hear about these studies more in
the debate.
Suffice it to say that the difference in outcome wasn’t statistically significant favors AF as
I understand it from the paper. Jag, tell me if I’ve got it right, means that there was
slightly more mortality in the AF patients compared to the sinus rhythm patients. But, the
difference wasn’t statistically significant. Okay?
AF is common in heart failure and presents multiple challenges. Novel atrial-specific
therapies will likely emerge to treat atrial fibrillation in the setting of heart failure.
Pulmonary vein isolation works even in patients with heart failure, and it’s preferable to
AV node ablation, plus CRT, at least in the absence of native dyssynchrony.
PVI and CRT are not mutually exclusive, okay? That’s something I think we’ll be talking
about in this session. When atrial fibrillation is present, CRT works, but only if the AV
node is ablated. I can make this bold statement because I wasn’t allowed to show the
data to support that.
And, AV node ablation also eliminates the risk of inappropriate ICD shocks for atrial
fibrillation when there’s rapid ventricular response. Thanks very much. Sorry to overtake
too much time.