Circulation August 16, 2022 Issue

This week, please join author Philipp Lurz and
Editorialist Daniel Burkhoff as they discuss the article
"Characteristics of Heart Failure With Preserved Ejection
Fraction Across the Range of Left Ventricular Ejection Fraction"
and the editorial "HF?EF: The Mysterious Relationship Between
Heart Failure and Ejection Fraction Continues."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-host. I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, Associate Editor, Director of the
Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


I just cannot wait to tell you about today's feature discussion,
Greg. It's about heart failure with preserved ejection fraction
and characteristics in the range of that ejection fraction that's
above 50%. So, okay. I know, I know. It's like, "Oh my gosh. Wow.
How much are we going to be talking about this ejection fraction
thing?" But I'm telling you, everybody has to listen to this.
It's really a big stride forward in our understanding of these
patients with heart failure and a higher ejection fraction. Plus
it includes one of my mentors from Mayo Clinic days, and I just
can't wait for everyone to hear this. But before we go there,
we've got really, really cool original papers in today's issue
too. Would you like to start first?


Dr. Greg Hundley:


You bet Carolyn, and I can't wait for that feature discussion,
especially this is a real area of your expertise. So listeners,
hold on for that feature discussion. Well, my first paper,
Carolyn, really pertains to physical activity. And Carolyn, the
study is led by Dr. Don Hoon Lee from the Harvard T.H. Chan
School of Public Health. And it evaluated a total of 116,000
adults from two large prospective US cohorts, the Nurse's Health
Study and the Health Professional's Follow up Study that took
place from 1988 to 2018. And they were examining self-reported
leisure time physical activity and assessed the association
between long term leisure time physical activity intensity and
all cause and cause specific mortality.


Dr. Greg Hundley:


Now Carolyn, two types of physical activity were assessed. First,
moderate physical activity and we're going to abbreviate that as
MPA and that was 150 to 300 minutes per week, which is really
recommended. Or second, vigorous physical activity for which it's
really recommended that one performs 75 to 150 minutes per week.
Now, Carolyn, as you know, some individuals accomplish both of
these in their routine, some neither, some one or the other. And
so it really remains unclear whether higher levels of long term
vigorous or moderate are independently or perhaps jointly
associated with lower mortality.


Dr. Carolyn Lam:


Oh, that's so interesting, Greg. Quick, quick, quick, tell us the
results.


Dr. Greg Hundley:


Right Carolyn. So the nearly maximum association with lower
mortality overall was achieved by performing approximately 150 to
300 minutes per week of long term leisure time vigorous physical
activity or 300 to 600 minutes per week of long term leisure time
moderate physical activity or an equivalent combination of both,
so mixing those minutes. Also Carolyn, very interestingly, higher
levels, suppose you go beyond those limits of either long term
leisure time vigorous physical activity of more than 300 minutes
per week or moderate physical activity of more than 600 minutes
per week did not show clearly further lower all cause
cardiovascular disease or non-cardiovascular disease mortality
and nor did they show harm. So if you went above those
thresholds, you really didn't experience greater harm.


Dr. Carolyn Lam:


Thanks, Greg. You know I'm going to be trying to apply that.
That's so cool. All right. Well the next paper refers to the
Cabana Trial, which I'll remind you is a trial in which catheter
ablation did not significantly reduce the primary endpoint of
death, disabling stroke, serious bleeding or cardiac arrest
compared to drug therapy by intention to treat, but did improve
quality of life and freedom from atrial fibrillation recurrence.
In Cabana, the heart failure subgroup, ablation appeared to
improve both survival and quality of life. The current paper led
by Dr. Mark and colleagues from Duke Clinical Research Institute
looked at the cost effectiveness of this ablation versus
angio-rhythmic drug therapy in atrial fibrillation and which was
a pre-specified Cabana secondary endpoint.


Dr. Greg Hundley:


Ah, Carolyn. So what did they find?


Dr. Carolyn Lam:


Well in this trial based economic evaluation, catheter ablation
was estimated to cost $57,893 per QALY or Quality Adjusted Life
Year gained compared to drug therapy in the overall cohort. And
this was primarily driven by improvement in quality of life. It
also cost $54,135 per QALY gained in the heart failure subgroup,
driven by both gains in quality of life and survival. In summary,
catheter ablation of atrial fibrillation was found to be
economically attractive compared to drug therapy in the Cabana
trial overall at present benchmarks of healthcare value in the US
and based on projected incremental qualities, but not live years
alone.


Dr. Greg Hundley:


Very nice Carolyn. Well, my next paper comes to us from the world
of Preclinical Science and it's corresponding author is Dr.
Swapnil Sonkusare from University of Virginia School of Medicine.
So Carolyn, calcium signals in smooth muscle cells contribute to
vascular resistance and control blood pressure. Now increased
vascular resistance in hypertension has been attributed to
impaired smooth muscle cell calcium signaling mechanisms. And in
this regard, transient receptor potential vanilloid four or TRPV4
smooth muscle cell ion channels are crucial calcium entry
pathways for smooth muscle cells. However, their role in blood
pressure regulation has not been identified.


Dr. Carolyn Lam:


Wow. TRPV4 smooth muscle cells. Cool Greg. So what did they find?


Dr. Greg Hundley:


Right, Carolyn. So these authors provide the first evidence that
TRPV4 smooth muscle cell channel activity elevates resting blood
pressure in normal mice. A1AR stimulation activated TRPV4 smooth
muscle cell channels through protein kinase calcium signaling,
which contributed significantly to vasoconstriction and blood
pressure elevation.


Dr. Greg Hundley:


Surprisingly, intraluminal pressure induced TRPV4 smooth muscle
cell channel activity, opposed vasoconstriction through
activation of calcium sensitive potassium channels indicating
functionally opposite pools of TRPV4 smooth muscle cell channels.
And so Carolyn, this team identified novel smooth muscle cell
calcium signaling nano domains that regulate blood pressure and
demonstrate impairment in hypertension.


Dr. Carolyn Lam:


Oh wow, Greg. Thank you so much for that. Well, let's cover the
other articles in today's issue. There's a primer by Dr. Jaffe on
High Sensitivity Cardiac Troponin and the 2021
AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation
and diagnosis of acute chest pain. There's also Research [Letter]
in there by Dr. Fordyce on the eligibility for non-invasive
testing based on the 2021 American Heart Association and ACC
guideline for the evaluation and diagnosis of chest pain,
implications from the Promise trial.


Dr. Greg Hundley:


Great Carolyn. Well, I've also got an exchange of letters to the
editor from Professors Benali and Professor Della Bella regarding
a previously published article, “Does Timing of Ventricular
Tachycardia Ablation Affect Prognosis in Patients with an
Implantable Cardioverter Defibrillator, Results from the
Multicenter Randomized Partita Trial.” And also there's a very
nice Perspective piece from Dr. Udelson entitled “Glucose Insulin
Potassium Therapy for Acute Myocardial Infarction, 50 years on
and Time for a Relook.” Well, Carolyn, I can't wait to hear more
of the discourse between you, the authors and editors on heart
failure and preserved ejection fraction.


Dr. Carolyn Lam:


Yay. Here we go. I'm so excited about today's feature discussion.
It's on my favorite topic, heart failure with preserved ejection
fraction. Although thanks to one of the authors, Dr. Daniel
Burkhoff of the editorial that accompanies it, I don't even know
how to pronounce, it's Heart Failure question mark Ejection
Fraction. I love it. How would you pronounce that?


Dr. Daniel Burkhoff:


Yeah, no, we debated how to pronounce it. HFQRef…a question mark?


Dr. Carolyn Lam:


HFQRef. Oh my goodness. What are we going to come up with next?


Dr. Daniel Burkhoff:


And we actually thought the editors would have a problem with
that. Whenever we put something cute in the title, we always get
knocked down. So we haven't yet got knocked down, so we'll see.


Dr. Carolyn Lam:


No, I'm not knocking you down.


Dr. Daniel Burkhoff:


But it just really emphasizes that we're in a very confusing time
now as it comes to heart failure and ejection fraction, that we
have to move on beyond ejection fraction. And although we have
these strict buckets and upper and lower limits for each range,
that maybe this is in a little bit of a way, doing us a
disservice and doing the patients at disservice in terms of
treatment.


Dr. Carolyn Lam:


That's really great. And everybody that was Dr. Daniel Burkhoff
from the Cardiovascular Research Foundation in New York. He's the
editorialist of today's feature paper. And I'm so excited that we
have the corresponding author of today's feature paper as well,
Dr. Philipp Lurz from Heart Center Leipzig in Germany. So first,
I mean, or second, heartfelt congratulations on this beautiful
paper, Philipp. If you could start with telling us all about what
you did and what you looked at and what made Dr. Daniel Burkhoff
call it now, Heart Failure, QREF?


Dr. Philipp Lurz:


Yeah. So thank you so much, first of all, obviously for having me
for the kind introduction and your kind words about our work. The
whole thing started with the observation that in recent drug
trials, the response in HFpEF patients to drugs which were before
proven to be quite successful in HFrEF actually showed a quite
heterogeneous response in HFpEF patients. And that there were
some patterns according to the range of ejection fractions. So it
seemed that those HFpEF patients with the lower ejection
fractions, they respond a little bit better to HFrEF medication
than those with a higher ejection fraction.


Dr. Philipp Lurz:


And HFpEF studies, they included patients within and ejection
fraction or 40 and above who normally would probably would
consider HFpEF to start with 50 and above. But even in those
truly HFpEF patients, so from 50 and anything above to 70, there
was a suggestion that there might be differences. 50 to 60 might
be something else and then 60 and above. And this is where we
started to look into our cohort and to group them according to
ejection fraction and see whether we can see some important and
clinically meaningful differences in morphology, obviously in
function, but then even also in terms of our biopsy results.


Dr. Philipp Lurz:


And that also implies that we did quite a deep phenotyping of our
patients. So we use imaging, echo obviously. We use magnetic
resonance imaging. We were able to acquire in a larger percentage
of that cohort, by the way, it was 56 patients in total, we were
able to get some left ventricular biopsies. And most importantly,
when it comes to the functional properties of the left ventricle,
we also acquired pressure volume loops. And that has the great
advantage that we obviously we can look at low dependent
parameters, but more important, also low independent in disease
of both systolic and diastolic function. And that's pretty much
what we did.


Dr. Carolyn Lam:


Oh my goodness. I mean, as an editor at Circulation, can I just
first tell you that's what really, really stood out? It's the
comprehensive, careful, in-depth characterization. It may be 56
patients, but MRI, echo, biopsies, exercise, PV loops. I mean, it
was a lot, a lot that you did. Could you boil it down to what you
found and maybe just to first clarify to the audience, how did
you bend the ejection fraction? And then what you found?


Dr. Philipp Lurz:


We divided the cohort in two groups. One with an ejection
fraction 50 to 60, and the other groups higher than 60% left
ventricular ejection fraction. We ended up in lower group, 21
patients, in the higher group with 35 patients. And they were
quite different. They had distinct features in terms of
morphology, means that the lower injection fraction group, they
had larger ventricles. That's probably what you would expect when
you group them according to eject fractions. So not that
surprising.


Dr. Philipp Lurz:


And at that point, and they had the same stroke volume. The low
ejection fraction group, you could say that they had a certain
degree of eccentric modeling, whereas those were the high
ejection fraction group, that concentric modeling. When we then
looked at the biopsies, the group with the low ejection fraction
group, so 50 to 60, they had higher percentage of myocardial
fibrosis at 15%.


Dr. Philipp Lurz:


And then on left ventricular biopsy, we saw that patients with a
high ejection fraction group, they had less myocardial fibrosis,
so more fibrosis in those with the lower ejection fraction group.
And this is really interesting because when we then look at the
real size of the pressure volume loop analysis, despite the fact
that the high ejection fraction group had less fibrosis, they had
the most stiff ventricles on pressure volume loop analysis. So
that's already a very important point because it illustrates once
again that we should not mistake fibrosis with stiffness, and
also not the other way around. There are other parameters which
can cause stiffness such as cellular stiffness, and it's not just
the extracellular matrix.


Dr. Philipp Lurz:


So that's an important point. Those patients with high ejection
fraction, they had the most stiff ventricles. They had the most
relevant limitations in left ventricular filling, so the most
marked diastolic dysfunction. We also looked at systolic
parameters and there we found that they had a very high
contractility. So this is the end systolic pressure volume
relationship or also called elastics and that's a marker for
contractility. So these ventricles with high ejection fraction,
they can contract very well. They have high contractivity. But
this is also a marker of systolic stiffness. So they stiff, both
in terms of diastolic properties, but also systolic properties.
And there, their most important limitation is the limitation in
filling.


Dr. Philipp Lurz:


The other group, injection fraction 50 to 60, they do have some
stiffness. Obviously we are talking about HFpEF. This is a
disease of a diastolic dysfunction. So they have increased
stiffness, but to a lesser extent. They can feel a little bit
better, but what we see there is a reduction in contractility, so
systolic properties. So you could argue that in some extent, that
group 50 to 60, they behave a little bit more like HFrEF. Whereas
those with high ejection fraction, they're completely different.
Very stiff, both doing diastolically and sistolly.


Dr. Carolyn Lam:


Thank you so much. Now I really have to get the gurus insight
into this. And of course by guru, I mean, Dr. Daniel Burkhoff.
First, I'm going to take this opportunity to share a little
private personal story that it's very hard for me to call Dr.
Burkhoff, "Dan", although if you will allow me it's because I was
a fellow when I first met Dr. Burkhoff. And one of my first
papers was actually communicating with Dr. Burkhoff trying to
draw these PV loops based on the noninvasive measurements that I
was obtaining at the Mayo Clinic in the Olmsted County Cohort.
And so this is just really making me smile. So Dan, if I may,
what do you make of all this? And if you could give us what you
think may be the clinical take home message.


Dr. Daniel Burkhoff:


Thank you so much, Carolyn. And also again, Philipp,
congratulations on really a really important paper. I think as
Carolyn was saying, one of the many things that impressed me was
the multifaceted aspects of the thorough evaluation using multi
modality characterization, which is in my mind, unprecedented,
especially for this particular group of patients. And you
summarized the main results very well. But to me, the thing that
really struck me and that we really tried to emphasize in our
editorial was the differential response to exercise, to hand grip
exercise in this point.


Dr. Daniel Burkhoff:


As you already said, and I don't think this could be understated,
that in the lower range, the 50 to 60, these patients were able
to fill, the ventricle was able to fill more, the end diastolic
pressure still went up significantly into an abnormal range,
which is of course is one of the requirements for the diagnosis
of HFpEF. But those patients, the end diastolic volume was able
to increase and that helped them to increase their cardiac
output.


Dr. Daniel Burkhoff:


In the higher EF group, the greater than 60, the end diastolic
pressure went up, but the volume did not increase. So the end
diastolic pressure volume relationship became higher elevated.
And this of course, was reminiscent of what was identified in the
early nineties by Dalane Kitzman. And really, he didn't make this
distinction between the lower half and the higher half. And we
had also in a paper that we did with David K and others, seen a
similar finding a couple years ago. And I think this is really,
to me, was the along with the apparently disparate findings on
myocardial biopsies with fibrosis going the wrong way, if you
will, as you already commented on. So this is at least for the
higher EF group, is identifying what I would refer to as really
true diastolic dysfunction.


Dr. Daniel Burkhoff:


That means that the patients can't fill, there really is some
problem why the EDP can go up, but the volume does not increase.
And this is obviously for future research, we have to understand
what is the difference between these two groups. There are
several speculations about why it might. For example, one thing
that has been proposed in the literature is the pericardial
restraints. If the heart is constrained in a tight pericardium,
the volume is recruited from the venous system, which is another
what I think is a very important part of this HFpEF phenotype,
but the heart is already constrained. That would elevate both the
CVP and the wedge pressure without concomitant increases in RV or
LV volumes, and therefore limit the ability to increase the
cardiac output.


Dr. Daniel Burkhoff:


Another alternative is delayed relaxation. That means a true
abnormality of active relaxation. The tau if you will, but I
believe in your study, if I remember correctly, the tau was not
that abnormal and did not really change very much in either
group. So it was harder to really pin it on an abnormality of
active relaxation. So that was one really, I think, really
important finding.


Dr. Daniel Burkhoff:


The second is now in the group 50 to 60 where they could fill,
one of the limitations of the study that you pointed out was that
there's no control group. So why this population, this HFpEF
population, the EDP increased, but the EDV the end diastolic
volume also increased, so what's different between those patients
and normals? That we don't really have an answer for yet. So that
would be one thing is to compliment these findings with results
in a true control group that does not have HFpEF.


Dr. Daniel Burkhoff:


So we still have this mystery of why does EDP go up in this
group? My perspective is not an abnormality of diastolly. It's
not a diastolic dysfunction, even though it's a HFpEF. I've been
trying to promote this idea for more than 20 years, that all
HFpEF is not an abnormality of diastolic ventricular properties.
There may be extra cardiac factors even beyond the pericardium in
this group. So I think these results are just further telling us
how complicated and individualized our approach to the
pathophysiology of these patients should be.


Dr. Daniel Burkhoff:


And also just one final comment, making a strict cutoff at 60% or
57% as we saw from Valsartan Cuba trial, Valsartan study, is
clearly also not going to do us justice. Let's say that we're
dealing with anyway, patients with two different
pathophysiologies. There's going to be a distribution of these
different mechanisms and there's going to be an overlap of these
distributions. So we need to start thinking about how we
individualize and characterize the pathophysiology in individual
patients. So maybe patients with EF of 55, certain patients with
EF 55 will not respond to Sacubitril- Valsartan and maybe some
patients with an EF of 62 will. So we need to go more deep into
the clinical characterization.


Dr. Daniel Burkhoff:


And methods that you use in particular, the pressure volume loop,
seem to separate, very nicely, these two different, at least two
different subtypes. So I think it's very exciting, and I think
people should really take notice of what you found and build on
this as a foundation and understand that we need to go deeper on
the clinical side to phenotype these patients.


Dr. Carolyn Lam:


Philip, what are your thoughts?


Dr. Philipp Lurz:


No, I think that the concept about stress and unstressed volume
is extremely important and fascinating, but that's where it gets
really complex because you could make the conclusion from our
results that especially the high ejection fraction group, they
are have a very high preload sensibility, which means that when
we reduce pre-load too much in them, they drop the stroke volume
very suddenly. So that's probably also the clinical question for
the future. There are many patients, HFpEF patients in whom we
should reduce stress volume and they can benefit from that.


Dr. Philipp Lurz:


But I also believe that there is a cord of patients, and those
are probably more those with high ejection fraction. They
actually, they could experience some harm if you reduce preload
too much because of the severe filling restrictions, because of
the inability to increase end diastolic volumes, especially as an
adaptation to exercise. And I think if we find out ways to
differentiate who will benefit from preload reduction and from
decongestion and who actually might experience even harm from
these interventions, then we are certainly one step further.


Dr. Carolyn Lam:


If I may, I just, I could go on forever, but I know that there's
going to be this question that the audience is immediately
thinking. Here we are going into the weeds, hemodynamics, we all
love it. In fact, I think we're all kind of a little bit geeky
about it, but then you've got, Emperor preserved, the Deliver
Trial sort of being positive in heart failure with ejection
fraction above 40. So, do we really need to understand the
different hemodynamic? What do you think is happening that this
sort of blanket benefit can occur?


Dr. Philipp Lurz:


I don't think that everyone will benefit. And I think that a
better understanding of the underlying pathophysiology will help
to even increase the rate of responders and dissect of those who
will not respond or we need a different therapy. Obviously here
we group patients according to ejection fraction. We just
discussed that this is a very rough way to characterize patients.
So the next step certainly would be to understand or to see
distinct patterns in left ventricular functional behavior
irrespective of ejection fraction. Because you might can skip
ejection fraction at one day, but the conclusion is not, at least
not in my opinion, that all heart failure is the same.


Dr. Carolyn Lam:


Nice. And Dan, what do you think?


Dr. Daniel Burkhoff:


Well, I think with STLT2 inhibitors, first of all, we're looking
forward to actually seeing the results from Deliver what the
details of it in terms of mortality versus hospitalizations and
quality of life. But with regard to HSGL2 inhibitors, I don't
think we know the mechanism. I mean, I've read about six papers
that definitively talk about different mechanisms of action. I
think we don't know. And even despite, let's say positive
studies, there's still a significant residual risk that these
patients have. So these are not the end of the story by any
means. I think this is the beginning of the story and there's
still going to be a lot to learn.


Dr. Daniel Burkhoff:


I think with SGLT2 inhibitors, I think it's difficult to identify
who is or how do you define a responder on an individual patient
basis? When we look at groups and you look at mortality and
hospitalizations, yes, you can identify them. But that group does
not overlap exactly with those who have an improvement in quality
of life. So I think that we're just at the beginning,


Dr. Daniel Burkhoff:


I do think that a deeper phenotyping is going to be the way to go
ultimately and I think we're going to need more therapies. Thanks
again, Carolyn for inviting me to do the editorial and to
participate in this. And I would really be remiss if I did not
mention the extraordinary contributions for Mickey Brener and
also Barry Borlaug who were equal contributors to this editorial
and the evaluation of this paper. So I'm really indebted to both
of them for this interpretations. And thank you again, Philipp,
for just a wonderful paper.


Dr. Carolyn Lam:


Couldn't have said it better and I just want to thank you once
again for providing that deeper phenotyping for opening the door.
Many of us said it again and again, this is the beginning and we
need more studies, frankly, in yours. I mean, I think Dr.
Burkhoff wants you to send normal, healthy people for MRI
biopsies, exercise, echo. I'm kidding, on PV loops, but it's
true. We need that data. We need the same and the HFrEF and
really just to understand the whole thing. I'm so excited about
what this paper opens up.


Dr. Carolyn Lam:


I am thrilled to see your editorial, Dan. I'm sure it's going to
be well received. Everyone who's listening to this, Pick up the
paper, pick up the editorial. Thank you so much for joining us
today. You've been listening to Circulation on the Run and from
Greg and I, don't forget to tune in again next week,


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2022. The opinions expressed by speakers in this podcast are
their own and not necessarily those of the editors or of the
American Heart Association. For more, please visit
hajournals.org.