Circulation October 22, 2019 Issue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. 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 for Circulation, from
the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn, our feature article, this issue reminds us of the
importance of the physical exam in patients with heart failure
and reduced ejection fraction involving those that were enrolled
in the PARADIGM-HF. Remember a trial of sacubitril/valsartan
versus ACE inhibition in those with a reduced ejection fraction?
Can't wait to hear more of the discussion of the importance of
that physical exam. Carolyn, how about you talk about your first
article?


Dr Carolyn
Lam:               
I will because this first paper reports a novel ventricular
tachycardia or VT ablation strategy guided by a voltage
independent mapping display during sinus rhythm.


Dr Greg
Hundley:            
Well, Carolyn, since many of us don't do VT ablations every day,
how about a little background on this one first?


Dr Carolyn
Lam:               
Substrate modification during sinus rhythm is actually the
mainstay ablation strategy for scar related VT. With the recent
trend being more extensive ablation, aimed to homogenize the
entire scar region. These authors are led by Dr Tung from the
University of Chicago Medicine Center for Arrhythmia Care, and
colleagues. They had hypothesized that a greater understanding of
the nature and characteristics of the scar would be most prone to
reentry, may actually improve the precision and yield of
ablation. Now, they had previously demonstrated that sites
critical for reentrant VT localized to regions of activation
slowing during sinus rhythm or so-called deceleration zones
rather than regions with latest activation. In the current study,
they aim to prospectively assess the outcomes of VT ablation
guided primarily by targeting these deceleration zones identified
by propagational analysis of ventricular activation during sinus
rhythm.


Dr Greg
Hundley:            
Interesting. What did they find, Carolyn?


Dr Carolyn
Lam:               
They studied 120 patients with scar related VT who are
prospectively enrolled in the U Chicago VT ablation registry
between 2016 and 2018, who underwent 144 ablation procedures for
scar related VT. They performed high density mapping during
baseline rhythm and identified the deceleration zones which all
localized to successful termination sites in 95% of cases. The
median total radio frequency application duration was 29 minutes
to target the deceleration zone, representing ablation of 18% of
the low voltage area. At a mean of 12 months, 70% freedom from VT
recurrence was achieved with an overall survival rate of 87%. A
novel voltage independent high-density mapping display may
further identify the functional substrate for VT during sinus
rhythm and guide targeted ablation thus obviating the need for
extensive radio frequency delivery.


Dr Greg
Hundley:            
Fantastic, Carolyn.


                                               
Well, my first paper is from Professor Mark Nicolls from Stanford
University. It's entitled Phenotypically Silent Bone Morphogenic
Protein Receptor 2 or Bmpr2 mutations, that predispose rats to
inflammation induced pulmonary arterial hypertension by enhancing
the risk for neointimal transformation. While being the most
common inherited risk factor for pulmonary arterial hypertension,
Bmpr2 germ line mutations only result in disease in 20% of
mutation carriers. A finding that suggest a second hit is
required to elicit vascular pathology. Transgenic mouse models of
Bmpr2 mutations were developed in this study to better understand
the relationship between these phenotypically silent gene
mutations and the predisposition to pulmonary arterial
hypertension.


Dr Carolyn
Lam:               
Huh. What did they find Greg?


Dr Greg
Hundley:            
In this new two hit model of disease, Bmpr2 mutant rats subjected
to pulmonary inflammation, developed severe pulmonary arterial
hypertension with vascular remodeling and the pulmonary arterial
endothelial cell transformation that occurred did so in three
phases. An initial apoptosis phase induced by exogenous LTB4.
Second, a proliferative phase relying on P38 mediated
noncanonical TGF-beta signaling. And then finally a terminal
inflammatory phase in which pulmonary arterial endothelial cells
utilized the canonical TGF-beta pathway, expressed mesenchymal
markers and produced LTB4, IL6 and NF-kappa beta signaling
molecules. The clinical implications include that in
phenotypically silent Bmpr2, haploinsufficient individuals, a
second hit of pulmonary inflammation may put them at risk for
subsequently developing pulmonary arterial hypertension. And this
lung inflammation while usually self-limited may cause durable
and inflammatory vascular lesions in these genetically
susceptible patients.


Dr Carolyn
Lam:               
Wow, that is super interesting. Thanks Greg for that great
summary.


                                               
Well, my next paper really looks at the temporal trends in
survival after pediatric in hospital cardiac arrest in the United
States. This is from Dr Holmberg from Beth Israel Deaconess
Medical Center and colleagues who performed an observational
study of hospitalized pediatric patients who received CPR from
January 2000 to December 2018 and were included in the Get With
the Guidelines resuscitation registry.


Dr Greg
Hundley:            
Carolyn, what did they find?


Dr Carolyn
Lam:               
They found that survival has improved for pediatric events
requiring CPR in the US with a 19% absolute increase in survival
for in hospital pulseless cardiac arrests and a 9% absolute
increase in survival for non-pulseless events between 2000 and
2018. However, survival from pulseless cardiac arrest appeared to
have reached a plateau following 2010. The increase in survival
over time is reassuring and perhaps provides some evidence for
the progress of quality improvement efforts. However, given the
plateau and survival following 2010, there is a continued need
for clinical focus and new interventions to improve outcomes of
pediatric in hospital cardiac arrests. And Greg, are you now
going to tell us what's in the mailbag?


Dr Greg
Hundley:            
Absolutely Carolyn. Professor Wei, from Harvard, provides a new
perspective on using the restricted mean survival time difference
as an alternative to the proportional hazards model and hazard
ratios for analyzing risk in clinical cardiovascular studies. In
another article, Eric Peterson from Duke provides a white paper
discussing randomized clinical trials versus EMR extracted data
to inform new therapies in cardiovascular disease. And he really
reviews what are the issues we need to overcome using these EMR
strategies? And on my mind piece from Dr Glenn Levine from
Baylor, discusses the role of psychological wellbeing as it
relates to cardiovascular disease. And then we have a large
series of letters in this issue.


                                               
First, Otmar Pfister and Kari Nytrøen, each have letters
regarding high intensity interval training. Dong-Vu Nguyen, asked
for several points of clarification regarding the utility of BNP
assessments in syncope and whether other metrics incorporating
clinical information could be useful. There's a corresponding
response from Christian Müller from the PRICIPLE study with great
discourse. And then finally an important research letter from Dr
Rodés-Cabau in Quebec, evaluates the left atrial occlude or
thrombus occurrence among eight centers in Canada and in this
letter provides data that suggests thrombi can occur in those
that have implanted left atrial occluders and raises
considerations for anticoagulation of these patients. Great set
of letters in this issue of the journal.


Dr Carolyn
Lam:               
Absolutely Greg and thanks for sharing that. Let's go onto our
feature discussion.


Dr Greg
Hundley:            
You bet.


                                               
Welcome everyone to discussion of our featured article and today
we have Senthil Selvaraj from University of Pennsylvania and our
own Mark Drazner, associate editor at Circulation from the
University of Texas Southwestern and we're going to be discussing
some very interesting results regarding the physical exam as
they've been generated from the PARADIGM heart failure trial. And
remember that's a prospective comparison of an Angiotensin
Receptor-Neprilysin inhibitor with an angiotensin converting
enzyme inhibitor to determine the impact of those two therapies
on all-cause mortality and also morbidity in heart failure.
Senthil, welcome to this discussion. We're very excited to have
the opportunity to discuss your article and I wonder before we
get started, could you tell us a little bit about the background
and the hypothesis for why you wanted to perform the study and
then afterwards tell us a little bit about the study population
and the methods.


Dr Senthil
Selvaraj:          I
think the impetus for this study torn out of the fact that we do
the clinical exam so often, and I think like many cardiology
clinicians in the community, we perform this so often, but we
don't know what the actual impact is of performing the clinical
exam. What I wanted to understand and the primary motivation was
to really understand what the change in the physical exam meant
in terms of subsequent prognosis. Does decreasing congestion
actually relate to improved cardiovascular outcomes? I think this
is an area that is hard to study by randomized controlled trials.
In my opinion I think there is not so much equipoise in
performing a trial of decongestion versus no decongestion. I
think this is sort of one way that we can understand
epidemiologic methods, whether lowering congestion improve
outcomes.


                                               
I had a number of other interesting analysis. I think the first
is we've had a number of studies that have evaluated the physical
exam, but I think that an updated analysis in a population
receiving contemporary management was particularly important,
particularly given the fact that the risk rad versus
insignificantly in the past couple of decades essentially related
to improvements in therapy. The second is we formed the physical
exam in conjunction with a number of other additional forensic
markers in the use of validated risk scores that to understand
those and have utility above and beyond this. For instance, can I
just check a natural aside and will that be doing a physical
exam. And I think while that's easier, I don't know that that
necessarily is the right thing to do. And that was another
motivation.


Dr Greg
Hundley:            
What was your overall study design and your study population?


Dr Senthil
Selvaraj:         
The overall study design was to use the PARADIGM-HF cohort. And
in our analysis, we did a time updated analysis, which is
different than many other analyses previously done. That means
that every single point that a patient goes into a clinical trial
visit, we updated their physical exam, possible because the study
investigators did perform an exam at each of these visits. And so
what we did was we used the physical exam and number of signs of
congestion as the time bearing covariate and looked at its
relationship to outcomes, but also just as importantly why might
think decreasing congestion or changing congestion has really
stuck out as very important about to want to feel better. And I
anything quantifying that relationship while it's intuitive I
think is also very important.


Dr Greg
Hundley:            
And just remind us who's in PARADIGM heart failure? Well what was
the study population? And just very quickly the randomization
arms?


Dr Senthil
Selvaraj:         
PARADIGM-HF was a randomized controlled international multicenter
trial of patients with heart failure ejection fraction which has
been defined in this study as less than or equal to 40%, near
two, three or four symptoms, elevated natriuretic peptides,
depending on the trial compared an angiotensin converting enzyme
inhibitor and Angiotensin Neprilysin inhibitor to control
valsartan.


Dr Greg
Hundley:            
Tell us what were your study results? And how did they pertain to
the outcomes that were gathered in PARADIGM-HF?


Dr Senthil
Selvaraj:         
We first divided our cohort based upon the total number of signs
and as might imagine increasing congestion was associated with a
number of adverse clinical features. We then looked at the
association between the number of signs and the efficacy
outcomes, which included a primary composite outcome of time to
heart failure, hospitalization as well as cardiovascular
mortality and then we individually looked at those as well as
all-cause mortality. And as we show in our paper, there was
really a striking relationship between time updated times of
congestion as well as all of the efficacy adjusted for baseline
natriuretic peptides which are available in all of our
participants in PARADIGM-HF as well as MAGGIC risk score and New
York Heart Association class to get at the question of whether
improving congestion, where the relationship congestion above and
beyond symptoms is still valid.


                                               
The other thing that we did is because we only looked at
natriuretic peptides at baseline is that we've formed a sub study
where we evaluated, since you had natriuretic peptides during
follow-up as well at the one month visit and eight month visit
and compare the utility of signs of congestion and outcomes and
you can still see that there was a significant relationship in
this sub analysis. The participants would complete NP data. We
further looked at relationship and congestion and quality of life
and there is a significant relationship such that for every sign
of congestion that you decrease, there is a five-point increase
in KCCQ, the quality of life score which some have considered to
be a clinically significant increase in times of congestion.


                                               
We also looked at the relationship between the treatment arm and
reduction of congestion as sacubitril/valsartan was associated
with significant reduction in clinical congestion, which has
mirrored its impact on natriuretic peptides as well. And finally
to understand whether reducing congestion was actually associated
with improved outcomes, we entered both the baseline congestion
and change of congestion into models that looked at the
relationship with outcomes and found that change of congestion
was a very strong predictor of outcomes even after baseline
congestion, which we interpreted to mean that reduction in
congestion was a mutable factor, and that reducing congestion is
actually associated with improved outcomes.


Dr Greg
Hundley:            
Signs of congestion on the physical exam, you had JVD, peripheral
edema, rales, and then an S3 and so you're adding those up and
making a score. And so when one of those particular findings
dropped off in terms of score, that's what you're indicating by
change in congestion, is that correct?


Dr Senthil
Selvaraj:         
That's really correct. We analyzed this in two methods. The first
is a dichotomous presence of a physical exam science. As you
said, the presence or absence of JVD, the presence or absence of
a DMO rales and an aspirate. The investigators also graded two of
those signs of congestion, which included a DMN rale that we
formed a complimentary analysis where we created a sign score
where we gave partial credits to gradations of the physical exam
and we saw very similar outcomes as well.


Dr Greg
Hundley:            
Mark Drazner at UT Southwestern has done a lot looking at the
importance of our physical exam and assessing patients with heart
failure. Mark, how do you feel the results of this study compare
with previously published works?


Dr Mark
Drazner:            
Thanks Greg. First, always a pleasure to join you on this and I
do want to congratulate Dr Selvaraj and his team on this
outstanding paper to generate considerable enthusiasm among the
editorial team and reviewers I'd say. It's a really interesting
study for several fold and you've heard a lot of the important
methods by Dr Selvaraj already. I would just highlight there've
been a number of previous studies that have looked at markers of
congestion from physical exam and showed that they had prognostic
utility, but a major question that has been addressed to me
personally and I think in the field, does that add any
independent information beyond just sending BMPR natriuretic
peptide level measurement?


                                               
And this analysis here as you've heard, one of the big advances
was that they were able to adjust for natriuretic peptide levels
and showed that the exam or the markers of congestion did add
independent prognostic information. I think that's an important
step forward, as is bringing the relevance again about the
markers of congestion and prognostic utility to patients being
receiving the most modern-day therapy including ARNI therapy,
which is unparalleled opportunity because of the PARADIGM trial
to look at that question. I think those two are really set this
paper. I think this is going to be a standard, this is the
standard for assessing prognostic utility congestion in heart
failure by far in the literature in my opinion.


Dr Greg
Hundley:            
What we're saying is that our following the patients and
identifying these physical exam changes during an initiation of
ARNI therapy can be really helpful in determining that particular
patient's long-term prognosis. Coming back to both of you, maybe
first Mark and then we'll come back to Senthil, what do you see
is the next study in this field? Both in terms of new therapies
in heart failure and the relationship of physical exam and then
also perhaps just briefly some thoughts on ARNI therapy.


Dr Mark
Drazner:            
I think this paper highlights the incredible importance of
congestion in modern day therapy. And there are a number of other
studies that looked at this recently, including there's an
analysis of TOPCAT preserved heart failure showing again
congestion being linked to adverse outcomes. I think that
question is resolved that even in modern day therapy. The next
step in my opinion is to understand why clinical congestion, the
pathway from clinical congestion to adverse outcomes. What are
the links? Can we target those links to try to interrupt that
cycle? And what is the most effective way to achieve
decongestion? We heard that now ARNI appears to be a mediator of
decongestion and we need more work on that I think. I would say
looking at the pathway from congestion to adverse outcomes and
then what is the optimal way to decongest our patients.


Dr Greg
Hundley:            
Very good. Senthil, do you have anything to add to that?


Dr Senthil
Selvaraj:          I
think that's great. I completely agree with Dr Drazner on this. I
think one question would be to understand truly as Dr Drazner
said, the optimal way to decongest patients and so for instance,
the way that we have traditionally done this is by increasing
diuretic. There are a number of experimental and novel ways that
we can decongest patients. I think one unanswered question
actually is does increasing a diuretic potentially at the expense
of activating the renin angiotensin aldosterone access, actually
afford benefit if you decongest patients. It's an analysis that I
think is ripe and timely and not been adequately addressed. I
think that that would be one potential way to go. And the second
is, I think as you mentioned in clinical trials, I think clinical
congestion may not be an outcome, a pre-specified outcome of
course. But I do think that it is an important outcome aside from
just looking at decreases in other surrogate markers such as
natriuretic peptides. It's easy to perform. It's collected on
many investigator visits during these trials and therefore these
are ripe analyses.


Dr Greg
Hundley:            
Listeners, we look forward to speaking with you next week and
have a great week.


Dr Carolyn
Lam:               
This program is copyright American Heart Association 2019.