Circulation March 29, 2022 Issue

This week, join authors Steven Lubitz and Associate
Editor Mark Link as they discuss the article "Screening for
Atrial Fibrillation in Older Adults at Primary Care Visits:
VITAL-AF Randomized Controlled Trial."


Dr. Carolyn
Lam:            


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


Dr. Greg
Hundley:          


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


Dr. Carolyn
Lam:            


Well, guess what we have for the featured discussion today, Greg.
It's about screening for atrial fibrillation in older adults at
primary care visits. Very, very important topic. And what we'll
be looking at is the vital AF randomized control trial. Ooh,
we're going to keep everyone in suspense here as we carry on and
discuss today's papers. Can I start?


Dr. Greg
Hundley:          


Absolutely.


Dr. Carolyn
Lam:            


Alright. This first paper is about infective endocarditis. Now,
we know that cardiac surgery often represents the only treatment
option in patients with infective endocarditis. However,
infective endocarditis surgery may lead to a sudden release of
inflammatory mediators, which is associated with the severity of
postoperative organ dysfunction. So, authors Dr. Doesnst from
Friedrich Schiller University of Jena in Germany, and colleagues,
decided to investigate the impact of hemo absorption during
infective endocarditis surgery on post-operative organ
dysfunction.


This multicenter, randomized, non-blinded controlled trial
assigned 288 patients undergoing cardiac surgery for infective
endocarditis to hemo absorption, which is integration of cytosorb
to the cardiopulmonary bypass or control. The primary outcome was
defined as the difference between the mean total postoperative
sequential organ failure assessment score, calculated maximally
to the ninth postoperative day, and the difference with the basal
score. Secondary outcomes were 30 day mortality, durations of
mechanical ventilation, basal presser and renal replacement
therapy. Cytokines were also measured in the first 50 patients.


Dr. Greg
Hundley:          


Interesting study, Carolyn. Wow. So, what are the results?


Dr. Carolyn
Lam:            


Yes, this trial involved a lot of work and results showed,
however, that there was a failure to demonstrate a reduction in
postoperative organ dysfunction, 30 day mortality, or any of the
clinically relevant secondary outcomes through intraoperative
hemo absorption. Although hemo absorption reduced plasma
cytokines at the end of cardiopulmonary bypass, there was no
difference in any of the clinically relevant outcomes.


Dr. Greg
Hundley:          


Great description, Carolyn. Well, my first paper comes to us from
the world of preclinical science. And Carolyn, the ascending
thoracic aorta, site of aneurysm formation, is populated by a
mosaic of medial and adventitial cells that are embryonically
derived from either the second heart field, or the cardiac neural
crest. Second heart field derives cells, populate areas that
coincide with the spatial specificity of thoracic aortopathies
that are often associated with aneurysms. And so, this study, led
by Dr. Alan Daugherty, from the University of Kentucky. Its
purpose was to determine whether and how second heart field
derived cells contribute to as sending aortopathies.


Dr. Carolyn
Lam:            


Wow, an important topic, Greg. What did the authors find?


Dr. Greg
Hundley:          


Okay. So, Carolyn, first, ascending aortic pathologies were
examined in patients with sporadic thoracic aortopathies and
angiotensin 2 infused mice. And so, the investigators found
several things. First, second heart field derived smooth muscle
cells and fibroblasts associate with angiotensin 2 induced aortic
pathologies. Second, angiotensin 2 induced a distinct fibroblast
sub-cluster that was less abundant for messenger RNAs related to
major extracellular components and TGF beta-ligands and
receptors, but more abundant for proliferative genes.


Third, TGFBR2 deletion in second heart field derived cells were
embryonically lethal, with significant dilatation of the outflow
tract in the mice. And finally, second heart field specific
deletion of LRP1 led to aortic pathologies in mice, supporting
the importance of second heart field derived cells in maintaining
ascending aortic wall integrity.


Dr. Carolyn
Lam:            


Wow. Could you just sum up the clinical implications for us,
Greg?


Dr. Greg
Hundley:          


Well, Carolyn, I knew you were going to ask me that. So, these
results indicate that heterogeneity of the embryonic origins of
smooth muscle cells and fibroblasts contributes to complex
mechanisms of vasculopathy formation, which should be considered
when investigating the pathogenesis of thoracic aortopathies.


Dr. Carolyn
Lam:            


Wow, thanks Greg. Well, my next study is also a translational
study, and this one provides a deeper understanding of insulin
regulation of cholesterol metabolism, and its disruption in type
one diabetes. So, this is from Dr. Biddinger from Children's
Hospital Boston and colleagues. In order to define the mechanisms
by which insulin controls plasma cholesterol levels, the authors
knocked down the insulin receptor, FOXO1, and the key bioacid
synthesis enzyme, CYP8B1, in mice. They measured bioacid
composition, cholesterol absorption, and plasma cholesterol. In
parallel, they measured markers of cholesterol absorption and
synthesis in humans with type one diabetes treated with ezetimibe
and statins in a double blind crossover study.


Dr. Greg
Hundley:          


Oh, wow, Carolyn. So, experiments in both animal models and in
human subjects. So, what did they find?


Dr. Carolyn
Lam:            


Insulin, by inhibiting FOXO1 in the liver, reduces 12 alpha
hydroxylated bio acids, reduces cholesterol absorption and
reduces plasma cholesterol levels. Thus, type one diabetes leads
to a unique set of derangement in cholesterol metabolism with
increased absorption rather than increased synthesis. These
derangements are reversed by ezetemibe, which is a cholesterol
absorption inhibitor, but not simvastatin, which is a cholesterol
emphasis inhibitor. So, taken together, these data suggest that a
personalized approach to lipid lowering in type one diabetes may
be more effective, and highlight the need for further studies
specifically in this group of patients.


Dr. Greg
Hundley:          


Nice, Carolyn. Well, we've got some other really interesting or
articles in the issue. And first, from the mail bag, there's a
Research Letter from Professor Bers, entitled "Empagliflozin
Reverses Late Sodium Current Enhancement and Cardiomyocyte
Proarrhythmia in a Translational Murray Model of Heart Failure
with Preserved Ejection Fraction." Carolyn, there's another
research letter from Professor Shu entitled, "Activation Of INKY
Cells at the Maternal Fetal Interface that Predisposes Offspring
to Cardiac Injury." Also, there's a really nice, in depth article
entitled, "Takasubo Syndrome Pathophysiology Emerging in Concepts
and Clinical Implications." And it's from Dr. Trisha Singh.


Dr. Carolyn
Lam:            


Nice. We also have an ECG challenge by Dr. Mugnai on “A
Tachycardia in Disguise” and a Perspective piece by Dr. Alexander
on “Equipoise in Clinical Trials: Enough Uncertainty [but] in
Whose Opinion?” Isn't that interesting? Wow, thanks, Greg. Now,
though, let's go on to this super exciting feature discussion on
screening for atrial fibrillation in older adults' primary care.


Dr. Greg
Hundley:          


You bet.


Well, listeners, we are here for the feature discussion, now, on
this March 29th issue. And we have with us Dr. Steve Lubitz, from
Mass General and Boston, and our own associate editor, Dr. Mark
Link, from University of Texas Southwestern Medical Center in
Dallas, Texas. Welcome, gentlemen.


So, Steve, we're going to start with you. Can you describe for us
some of the background information that went into the construct
of your study, and then what was the hypothesis that you wanted
to address?


Dr. Steven
Lubitz:           


Sure. Well, thanks for the opportunity to talk with you today
about our work. So, as we know, AFib is a common and more bitter
arrhythmia. And the first manifestation of AFib can be stroke in
a substantial number of individuals. Strokes from atrial
fibrillation or debilitating, but they can be prevented using
oral anticoagulants if we know who has atrial fibrillation.


But atrial fibrillation can be a symptomatic and it's possible,
therefore, that screening pre-AFib could lead to new diagnoses
and ultimately improve outcome by enabling stroke prevention.
Point of care screening for AFib has been embraced by some
guidelines for individuals age 65 or older, such as those in
Europe, and mobile technology has now evolved and enables rapid
mask screening using handheld ECGs, single lead ECGs, which
obviates the need and expense of performing 12-lead ECGs to
screen for AFib.


Nevertheless, though, some guidelines have suggested that data
are insufficient to recommend screening AFib using ECGs, such as
those from the United States Preventative Services Task Force. We
tested whether screening individuals age 65 or older at the time
of a primary care clinic visit using a single lead ECG would lead
to an increased rate of detection of AFib in contemporary United
States practices.


Dr. Greg
Hundley:          


Very nice. And so, maybe describe for us this task force, and
also what was your study design and, again, your study
population?


Dr. Steven
Lubitz:           


Sure. So, specifically our study design, we performed a cluster
randomized control trial in which primary care practice clinics
were randomized to the screening intervention or to usual care,
and patients aged 65 or older arriving for a primary care visit
with their provider were eligible for participation. Patients
were offered screening by practiced medical assistants at the
time of their vital sign assessments, and screening was
performed, if they consented, within a live core cardio mobile
single ECG device, which was affixed to an iPad and stationed in
the clinic.


The results of the screening were made available to the providers
at the time of the visit, and then the provider was able to make
any and all decisions about subsequent management, confirmation
or treatment. The primary outcome was a new diagnosis of Afib
made in the medical record at one year following the start of the
screening intervention, and the outcome was ascertained using the
electronic health record and then manually adjudicated. We
powered the study to detect a difference of nearly 0.5% in the
rate of atrial fibrillation diagnoses at 12 months between the
screening and usual care arms.


Dr. Greg
Hundley:          


And how many patients did you enroll? And then what were your
study results?


Dr. Steven
Lubitz:           


Well, eight practices were randomized to the screening arm and
eight practices to the usual care arm. And in total, that equated
to about 15000 patients without a history of atrial fibrillation
in the screening arm and 15000 patients in the control arm
without a history of atrial fibrillation. The mean age was about
74, about 60% were female, 82% were white. And the mean chad-vad
score was 3.4.


We observed several main findings. The first is that, of the
individuals in the screening arm, 91% were screened at least
once. And this is the largest point of care screening study to
date. The rate of screening in the intervention arm was
substantially greater than any other contemporary trial, point of
care, single ECG screening. We think that high rate of compliance
with the intervention reflects patient enthusiasm for screening
and a widespread feasibility of incorporating single ECGs into
the routine vital sign practice workflow.


Secondly, the primary endpoint, however, incidence of new AFib
diagnoses at 12 months, was 1.72% in the screening arm, and 1.59%
in the usual care arm, which equates to a risk difference of
.13%. That was not statistically significant in the overall
sample. We observed a substantial difference in new AFib
diagnoses among those aged 85 or older in pre-specified subgroup
analyses, 5.56% in the screening arm and 3.76% in usual care arm,
which corresponds to a risk difference of 1.8%, where a number
needed a screen of about 55, raising the possibility that point
of care single ECG screening among the oldest and highest risk
individuals might be effective. But this finding warrants future
study.


Third, we observed a shift in the location of diagnosis. So, they
fit with a higher likelihood of diagnosis at a primary care
practice encounter in the screening arm, as compared to the usual
care arm, which is as expected. And the implications on
downstream management pathways, cost of care, other downstream
work flows is unknown at the moment.


And lastly, we observed it in anticoagulation use was high, even
among those with AFib diagnosed in the screening arm, which is a
reassuring finding, suggesting that clinicians recognized that AF
detected using this single lead point of care screening is likely
to represent high burden, persistent AF that carries a
substantial risk of stroke.


Dr. Greg
Hundley:          


Very nice. Well, Mark, I know you review many papers for us here
at Circulation. What attracted you to this particular paper?


Dr. Mark Link:   


This issue of point of care screening for AFib is a very hot
topic. We all know that clinically diagnosed AFib carries with it
a high risk of stroke, but what we don't know is incidentally
found Afib, or nonclinically found Afib, what does that mean?
This was one of the largest, if not actually the largest, study
of point of care screening. And the i-cors are a very accurate
device, or reasonably accurate device. So, we thought it's an
important contribution to the literature. I think it surprised
the authors, as well as us, there wasn't a difference in the
diagnosis of AFib between the two arms. I think all of us
would've expected to see that. But we're still learning a lot
about point of care screening, and we're not to the point where
we know what to do yet.


Dr. Greg
Hundley:          


And Mark, what are some of your thought? Steve raised the point
that, in that subgroup, greater than age 85, any additional
insights there?


Dr. Mark Link:   


Yeah. I think that, if you can enrich your group with people that
are more likely to have AFib, and the older you get, the more
likely you are to have AFib, you are more likely to find Afib.
But then treating people over age 85 also becomes a little bit
riskier, with both anticoagulants and antirhythmic drugs and
ablation.


Dr. Greg
Hundley:          


Great points. Well, Steve, coming back to you, what do you see as
the next study to be performed, really, in this sphere of
research?


Dr. Steven
Lubitz:           


Thanks. I think I proposed two additional lines of inquiry. At
first, I think our hypothesis generating observation to the point
of care screening with a single EDCG can lead to higher rates of
AFib detection among the oldest individuals, age 85 or older,
with a small number needed to screen warrants, replication, and
the downstream implications of that on stroke and bleeding merit
further evaluation.


I think secondly, given the proliferation of wearable technology,
future studies should examine the effectiveness of detecting
perccismal atrial fibrillation for preventing downstream adverse
events, including stroke. This point of care screening is likely
to detect the highest burden persistent forms of atrial
fibrillation in contrast to some of the wearable technology, like
consumer wearable technology, that might detect paroxysmal atrial
fibrillation, more commonly.


Dr. Greg
Hundley:          


Ah, great point. And Mark, how about you? Anything to add? What
future study do you see needs to be performed in this space?


Dr. Mark Link:   


It's clear from a number of studies that the longer that you
monitor someone, the more likely you are to get a diagnosis of
AFib. And that's pretty clear. This was a 30 second monitor. We
have a number of studies that have shown two week and ILS
monitoring is far more likely to get a diagnosis of AFib. But
what we don't know is, if making that diagnosis of AFib makes any
difference on ultimate outcomes. That's the studies that we need
to see, is does treatment of incidentally found AFib improve
clinical care.


Dr. Greg
Hundley:          


Very good. Well, listeners, we want to thank Dr. Steve Lubitz
from Mass General in Boston, and also Dr. Mark Link from UT
Southwestern in Dallas, bringing us results from this study
indicating that screening for atrial fibrillation using a single
lead EKG at a primary care visit did not affect new atrial
fibrillation diagnoses among those that were aged 65 years or
older. There was, perhaps, a difference in those aged greater
than 85 years, but more research is to come in that space. And,
of course, looking for peroxisomal AFib with handheld devices is
another area you yet to be investigated.


Well, on behalf of Carolyn and myself, we want to wish you a
great week and we will catch you next week, On the Run.


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 ahajournals.org.